Process for arylating or vinylating or alkynating a nucleophilic compound

ABSTRACT

The present invention concerns a process for arylating or vinylating or alkynating a nucleophilic compound. More particularly, the invention concerns arylating nitrogen-containing organic derivatives. The arylating or vinylating or alkynating process of the invention consists of reacting a nucleophilic compound with a compound carrying a leaving group and is characterized in that the reaction is carried out in the presence of an effective quantity of a catalyst based on a metallic element M selected from groups (VIII), (Ib) and (IIb) of the periodic table and at least one ligand comprising at least one imine function and at least one supplemental nitrogen atom as the chelating atoms.

[0001] The present invention relates to a process for arylating orvinylating or alkynating a nucleophilic compound.

[0002] More particularly, the invention relates to arylatingnitrogen-containing organic derivatives.

[0003] Many important compounds exist in the agrochemical andpharmaceutical fields, for example arylhydrazines, which result fromarylating a nucleophilic compound by creating a carbon-nitrogen bond.

[0004] A conventional arylation method consists of carrying out theUllmann reaction (Ullmann F. and Kipper H., Ber. Dtsch. Chem. Ges. 1905,38, 2120-2126), by prolonged heating of the reagents at hightemperature, in the presence of catalytic or stoichiometric copper. Thereactions are usually limited to using aryl iodides and their yields arereduced by competitive formation of biaryl homocoupling products.

[0005] Arylation reactions require a catalyst; a number of types ofcatalyst have been described.

[0006] Palladium was used by Buchwald et al., in particular to carry outindole arylation (Org. Lett. 2000, 2, 1403-1406), in the presence of abase in toluene at 80° C.-100° C. Generally, the yields aresatisfactory, but the reaction temperature is still high for this typeof palladium-based catalyst.

[0007] Copper has also been used (Chiriac et al., Rev. Roum. Chim. 1969,14, 1263-1267) to carry out arylation of sodium salts and pyrazoles byiodobenzene in the presence of a catalytic quantity of copper under DMFreflux. The conditions described are very severe, the temperature is153° C. and the reaction period is very long at 30 to 40 hours.

[0008] Beletskaya et al. (Tetrahedron Lett. 1998, 39, 5617-5622)proposed a combination of palladium and copper when N-arylatingbenzotriazole. The presence of copper is indispensable to controllingthe selectivity of the reaction. The catalyst is a phase transfercatalyst which is not easy to use on an industrial scale.

[0009] International patent WO-A-98/00399 proposes the use of a nickelcatalyst, but this has proved to be of little effect when arylatingheterocycles such as imidazole.

[0010] Chan et al. also described (J. Chem. RES. (S) 2000, 367-369) thearylation of azoles from diaryliodonium salts in the presence of acobalt catalyst under phase transfer conditions.

[0011] Buchwald et al. (J. Am. Chem. Soc. 2001, 123, 7727-7729) recentlydeveloped a method for arylating nitrogen-containing nucleophilescatalysed by copper. Its catalytic system, composed of a catalyst thatis insensitive to air, cuprous iodide and thetrans-1,2-diaminocyclohexane ligand, allows heterocycles such aspyrazoles, indoles, carbazole, pyrrole, indazole, imidazole,phthalazinone and 7-azaindole to be arylated in dioxane at 110° C.

[0012] The disadvantage of that process is that the temperature is stillhigh when arylation is carried out by aryl chlorides or even by aryliodides.

[0013] The present invention aims to provide a process that overcomesthe disadvantages cited above and which is applicable to a very largenumber of nucleophiles.

[0014] We have now discovered, and this constitutes the subject matterof the present invention, a process for arylating or vinylating oralkynating a nucleophilic compound, consisting of reacting said compoundwith a compound carrying a leaving group, characterized in that thereaction is carried out in the presence of an effective quantity of acatalyst based on a metallic element M selected from groups (VIII), (Ib)and (IIb) of the periodic table and at least one ligand comprising atleast one imine function and at least one supplemental nitrogen atom aschelating atoms.

[0015] Throughout the description of the present invention, the term“arylation” is used in its broad sense since it is envisaged that thecompound employed carries a leaving group which is either of theunsaturated aliphatic type, or of the carbocyclic aromatic orheterocyclic type.

[0016] The term “nucleophilic compound” means an organic hydrocarboncompound that may be acyclic or cyclic and comprises at least one atomcarrying a free electron pair which may or may not carry a charge,preferably a nitrogen, oxygen, sulphur, phosphorus or carbon atom.

[0017] The term “imine function” means a functional group comprising anitrogen atom bonded to a carbon atom via a double bond.

[0018] The term “other supplemental nitrogen atom” means a nitrogen atomthat can be carried by a further imine function and/or by a functionalgroup such as an amine, amide, urea, nitrile, guanidine, sulphonamide,phosphinamide group and/or a nitrogen atom carrying a free electron pairincluded in a saturated, unsaturated or aromatic cycle.

[0019] As mentioned above, the nucleophilic compound comprises at leastone atom carrying a free electron pair, which can be carried by afunctional group.

[0020] Examples of functional groups comprising said atoms that can bementioned are:

[0021] In a further variation of the invention, the nucleophiliccompound comprises at least one nitrogen atom carrying a free electronpair included in a saturated, unsaturated or aromatic cycle; the cyclegenerally contains 3 to 8 atoms.

[0022] It should be noted that when the nucleophilic compound comprisesa functional group, examples of which were given above, which carriesone or more negative charges, said compound is then in its salt form.The counter-ion is generally a metallic cation such as an alkali metal,preferably sodium or lithium, or an alkaline-earth metal, preferablycalcium, or the residue of an organometallic compound such as amagnesium or zinc compound.

[0023] A first advantage of the process of the invention is that it iscarried out at moderate temperatures.

[0024] A further advantage is that a wide range of arylation agents fornucleophiles can be used, not only aryl iodides, but also aryl bromides.

[0025] A still further advantage of the process of the invention is thepossibility of using copper rather than palladium as the catalyst,bringing an additional economic advantage.

[0026] In accordance with the process of the invention, the catalyst isassociated with a ligand which is polydentate, at least bidentate,tridentate or even tetradentate, and which comprises the atoms definedabove in the description of the invention.

[0027] A first category of ligands for carrying out the process of theinvention is constituted by hydrazone type ligands, in particular thosewith formula:

[0028] in which formulae:

[0029] one of groups R_(a) and R_(b) can comprise at least one nitrogenatom or a group comprising a nitrogen atom;

[0030] R_(a) and R_(b) independently represent a hydrocarbon groupcontaining 1 to 20 carbon atoms, which may be a linear or branched,saturated or unsaturated, acyclic aliphatic group; a monocyclic orpolycyclic, saturated, unsaturated or aromatic carbocyclic orheterocyclic group; or a concatenation of said groups;

[0031] or R_(a) and R_(b) can be bonded to constitute, with the carbonatoms carrying them, a monocyclic or polycyclic, saturated orunsaturated carbocyclic or heterocyclic group containing 3 to 20 atoms;

[0032] R_(c) represents an alkyl group, preferably C₁ to C₁₂; an alkenylor alkynyl group, preferably C₂ to C₁₂; a cycloalkyl group, preferablyC₃ to C₁₂; an aryl or arylalkyl group, preferably C₆ to C₁₂, an amidogroup —CO—NH₂; an amido group substituted with one or two alkyl groups,preferably C, to Cl₂; and/or an alkenyl or alkynyl group, preferably C₂to C₁₂; and/or a cycloalkyl group, preferably C₃ to C₁₂; and/or an arylor arylalkyl group, preferably C₆ to C₁₂.

[0033] As mentioned above, at least one of groups R_(a) and R_(b)comprises a n atom or a group containing a nitrogen atom; examples thatcan be cited are groups such as amino, amido, . . . . The NH₂ group ispreferred.

[0034] In formulae (Ia₁) and (Ia₂), the different symbols can inparticular have the meanings given below.

[0035] Thus, R_(a) and R_(b) can independently represent a linear orbranched, saturated or unsaturated, acyclic aliphatic group.

[0036] More precisely, R_(a) and R_(b) preferably represent a linear orbranched, saturated acyclic aliphatic group, preferably C₁ to C₁₂, andmore preferably C₁ to C₄.

[0037] The invention does not exclude the presence of an unsaturatedbond on the hydrocarbon chain such as one or more double bonds, whichmay or may not be conjugated.

[0038] The hydrocarbon chain can optionally be interrupted by aheteroatom (for example oxygen, sulphur, nitrogen or phosphorus) or by afunctional group provided that it does not react, in particular, a groupsuch as —CO—.

[0039] The hydrocarbon chain can optionally carry one or moresubstituents (for example halogen, ester, amino or alkyl and/orarylphosphine) provided that they do not interfere.

[0040] The linear or branched, saturated or unsaturated acyclicaliphatic group can optionally carry a cyclic substituent. The term“cycle” means a saturated, unsaturated or aromatic carbocyclic orheterocyclic cycle.

[0041] The acyclic aliphatic group can be connected to the cycle via acovalent bond, a heteroatom or a functional group such as oxy, carbonyl,carboxyl, sulphonyl, etc. . . . .

[0042] Examples of cyclic substituents that can be envisaged arecycloaliphatic, aromatic or heterocyclic substituents, in particularcycloaliphatic substituents containing 6 carbon atoms in the cycle orbenzenic, said cyclic substituents themselves optionally carrying anysubstituent provided that they do not interfere with the reactionsoccurring in the process of the invention. Particular mention can bemade of C₁ to C₄ alkyl or alkoxy groups.

[0043] More particular aliphatic groups carrying a cyclic substituentinclude cycloalkylalkyl groups, for example cyclohexylalkyl, orarylalkyl groups, preferably C₇ to C₁₂, in particular benzyl orphenylethyl.

[0044] In group formulae (Ia₁) and (Ia₂), groups R_(a) and R_(b) canalso independently represent a carbocyclic group that is saturated orcontains 1 or 2 unsaturated bonds in the cycle, generally C₃ to C₈,preferably with 6 carbon atoms in the cycle; said cycle can besubstituted. A preferred example of this type of group that can be citedis cyclohexyl, optionally substituted with linear or branched alkylgroups containing 1 to 4 carbon atoms.

[0045] Groups R_(a) and R_(b) can independently represent an aromatichydrocarbon group, in particular betweeic with general formula (Fl):

[0046] in which:

[0047] q represents a whole number from 0 to 5;

[0048] Q is a group selected from a linear or branched C₁ to C₆ alkylgroup, a linear or branched C₁ to C₆ alkoxy group, a linear or branchedC₁ to C₆ alkylthio group, a —NO₂ group, a —CN group, a halogen atom or aCF₃ group.

[0049] R_(a) and R_(b) can also independently represent a polycyclicaromatic hydrocarbon group with cycles that can between them formortho-condensed or ortho- and peri-condensed systems. A more particularexample that can be cited is a naphthyl group; said cycle can besubstituted.

[0050] R_(a) and R_(b) can also independently represent a polycyclichydrocarbon group constituted by at least 2 saturated and/or unsaturatedcarbocycles or by at least 2 carbocycles only one of which is aromaticand forming ortho- or ortho- and peri-condensed systems between them.Generally, the cycles are C₃ to C₈, preferably C₆. More particularexamples that can be cited are the bornyl group and thetetrahydronaphthalene group.

[0051] R_(a) and R_(b) can also independently represent a saturated,unsaturated or aromatic heterocyclic group in particular containing 5 or6 atoms in the cycle, including one or two heteroatoms such as nitrogenatoms (not substituted with a hydrogen atom), sulphur or oxygen; thecarbon atoms of this heterocycle can also be substituted.

[0052] R_(a) and R_(b) can also represent a polycyclic heterocyclicgroup defined as either a group constituted by at least two aromatic ornon aromatic heterocycles containing at least one heteroatom in eachcycle and forming ortho- or ortho- and peri-condensed systems betweenthem, or a group constituted by at least one aromatic or non aromatichydrocarbon cycle and at least one aromatic or non aromatic heterocycleforming between them ortho- or ortho- and peri-condensed systems; thecarbon atoms of said cycles can optionally be substituted.

[0053] Examples of heterocyclic type groups R_(a) and R_(b) that can becited include furyl, thienyl, isoxazolyl, furazannyl, isothiazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrannyl, phosphino and quinolyl,naphthyridinyl, benzopyrannyl or benzofurannyl groups.

[0054] The number of substituents present on each cycle depends on thecarbon condensation of the cycle and on the presence or otherwise of anunsaturated bond on the cycle. The maximum number of substituents thatcan be carried by a cycle can readily be determined by the skilledperson.

[0055] R_(a) and R_(b) can be connected to constitute, with the carbonatoms carrying them, a monocyclic or polycyclic, saturated, unsaturatedor aromatic carbocyclic or heterocyclic group containing 3 to 20 atoms,comprising two or three ortho-condensed cycles which means that at leasttwo cycles have two carbon atoms in common. In the case of polycycliccompounds, the number of atoms in each cycle is preferably in the range3 to 6. R_(a) and R_(b) preferably form a cyclohexane or fluorenonecycle.

[0056] In formulae (Ia₁) and (Ia₂) for hydrazone type ligands, groups RCpreferably represent a hydrogen atom or a C₁-C₄ alkyl group, an amidogroup, or an amido group substituted with a C₁-C₄ alkyl group or with anamino group

[0057] Preferred hydrazone type ligands have formula (Ia₁) or (Ia₂) inwhich R_(c), which may be identical or different, represent a hydrogenatom or a methyl group and R_(a) represents one of the following groups:

[0058] in which R_(s) represents an alkyl or alkoxy group, preferably C₁to C₄, or an amino group which may or may not be substituted with analkyl group, preferably C₁ to C₄.

[0059] Hydrazone type ligands are produced by reacting:

[0060] an aldehyde or ketone with the following formulae:

[0061] in which formulae (IIa₁) or (IIa₂), R_(a), and R_(b) have themeanings given in formulae (Ia₁) or (Ia₂);

[0062] with a hydrazine or derivative with formula (IIa₃), preferablyhydrazine, N-methylhyddrazine or N,N-dimethylhydrazine:

[0063] in which formula (IIa₃), R_(c), which may be identical ordifferent, have the meanings given in formulae (Ia₁) or (Ia₂).

[0064] Preferred hydrazone type ligands used in the process of theinvention contain a nitrogen atom supplied by the pyridyl group of apyridylaldehyde residue. They are preferably obtained by reacting apyridylaldehyde with a hydrazine or a N-substituted or N,N-disubstitutedhydrazine, preferably substituted with an alkyl group containing 1 to 4carbon atoms.

[0065] Examples of preferred ligands are given below:

[0066] A further category of ligands that is suitable for carrying outthe invention is formed by tetradentate ligands:

[0067] in which formulae:

[0068] R_(a), which may be identical or different, have the meaningsgiven in formulae (Ia₁) and (Ia₂);

[0069] R_(b), which may be identical or different, have the meaningsgiven in formulae (Ia₁) and (Ia₂);

[0070] Ψ represents a HN—CO—NH— group or a skeleton with general formula(F₂) or (F₃):

[0071] in which formulae (F₂) and (F₃):

[0072] R_(f) and R₉ independently represent a hydrocarbon groupcontaining 1 to 20 carbon atoms, which may be a linear or branched,saturated or unsaturated acyclic aliphatic group; a monocyclic orpolycyclic, saturated, unsaturated or aromatic carbocyclic orheterocyclic group; or a concatenation of said groups;

[0073] or R_(f) and R_(g) can be bonded together to constitute, with thecarbon atoms carrying them, a carbocyclic or heterocyclic groupcontaining 3 to 20 atoms, which may be saturated, unsaturated,monocyclic or polycyclic;

[0074] Ar₁ and Ar₂ independently represent two substituted or nonsubstituted aromatic, carbocyclic or heterocyclic cycles which may ormay not be condensed, which may carry one or more heteroatoms;

[0075] x and y respectively represent the two bonds between the skeletonshown as ψ and the imine groups.

[0076] In formulae (Ib₁) and (Ib₂), symbols R_(a) and R_(b) can have themeanings given for formulae (Ia₁) and (Ia₂).

[0077] Preferred tetradentate ligands have formulae (Ib₁) or (Ib₂) inwhich R_(b) represents a hydrogen atom and R_(a) represents one of thefollowing groups:

[0078] in which R_(s) represents an alkyl or alkoxy group, preferably C₁to C₄, or an amino group which may or may not be substituted with alkylgroups, preferably C₁ to C₄.

[0079] In formulae (F2) and (F3), symbols R_(f) and R_(g) can have themeanings given for R_(a) and R_(b) in formulae (Ia₁) and (Ia₂).

[0080] Preferably, R_(f) is identical to R_(g).

[0081] Further, R_(f) and R_(g) can also be bonded together to representsaturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclicor heterocyclic groups, preferably bicyclic, which means that at leasttwo cycles have two carbon atoms in common. In the case of polycycliccompounds, the number of carbon atoms in each cycle is preferably in therange 3 to 6.

[0082] R_(f) and R_(g) can be bonded to constitute, with the carbonatoms carrying them, a saturated or unsaturated, monocyclic orpolycyclic, carbocyclic or heterocyclic group containing 3 to 20 atoms,preferably a cyclohexane type cycle.

[0083] Illustrative examples of groups ψ that can be mentioned are thefollowing cyclic groups:

[0084] Particularly advantageous compounds have general formula (F2) inwhich:

[0085] R_(f) and R_(g) both represent a phenyl or naphthyl group;

[0086] R_(f) and R_(g) are bonded together to constitute a cycle such ascyclohexane with the carbon atoms carrying them.

[0087] In formula (F₃), Ar₁ and Ar₂ together represent an aromatic groupwhich can be a carbocycle containing 6 to 12 carbon atoms or aheterocycle containing 5 to 12 atoms.

[0088] In the following description of the present invention, the term“aromatic” designates the conventional idea of aromaticity as defined inthe literature, in particular J. March, “Advanced Organic Chemistry”,4^(th) edition, John Wiley & Sons, 1992, pp. 40 ff.

[0089] Within the context of the present invention, the aromaticderivative can be monocyclic or polycyclic.

[0090] In the case of a monocyclic derivative, it can comprise one ormore heteroatoms in its cycle selected from nitrogen, phosphorus,sulphur and oxygen atoms. A preferred mode uses nitrogen atoms notsubstituted with a hydrogen atom.

[0091] Illustrative examples of monocyclic heteroaromatic derivativesthat are suitable for use in the present invention that can be cited arepyridine, pyrimidine, pyridazine and pyrazine derivatives.

[0092] The carbon atoms of the aromatic derivative can also besubstituted. Two neighbouring substituents on the aromatic cycle canalso, together with the carbon atoms carrying them, form a hydrocarboncycle, preferably aromatic, and can if necessary comprise at least oneheteroatom. The aromatic derivative is then a polycyclic derivative.

[0093] Illustrative examples of this type of compound that can be citedare naphthalene derivatives, quinoline derivatives and isoquinolinederivatives.

[0094] Representative examples of compounds with general formula (F₃)that can in particular be cited are those in which Ar₁ and Ar₂ togetherform either a group deriving from a diphenyl-2,2′-diyl group, or adinaphthyl-2,2′-diyl group.

[0095] The following cyclic groups constitute illustrative examples ofgroups ψ:

[0096] Ligands with formulae (Ib₁) or (Ib₂) are known products.

[0097] They are obtained by reacting:

[0098] an aldehyde or ketone with the following formulae:

[0099] in which formulae (IIb₁) or (IIB₂), R_(a) and R_(b) have themeanings given in formulae (Ia₁) or (Ia₂);

[0100] with a diamine or with formula (IIb₃):

H₂N-ψ-NH₂  (IIb₃)

[0101] in which formula (IIb₃), ψ has the meaning given in formulae(Ib₁) or (Ib₂) and represents a group —HN—CO—NH— or a skeleton withgeneral formula (F₂) or (F₃).

[0102] Preferred tetradentate type ligands used in the process of theinvention contain a nitrogen atom carried by the pyridyl group of apyridylalkdehyde residue. They preferably result from reactingpyridylaldehyde with urea, 1,2-cyclohexanediamine or1,2-diphenylethylenediamine.

[0103] Examples of preferred ligands are given below:

[0104] A further category of ligands that can be used in the inventionis formed by bidentate ligands with formula:

[0105] in which formula:

[0106] R_(a), which may be identical or different, have the meaningsgiven in formulae (Ia₁) and (Ia₂);

[0107] Φ represents:

[0108] a covalent bond;

[0109] an alkylene group with formula:

[0110] in which R_(c), R_(d), which may be identical or different,represent:

[0111] a hydrogen atom;

[0112] a linear or branched alkyl group containing 1 to 12 carbon atoms,optionally carrying a halogen atom, preferably 1 to 4 carbon atoms, suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl ortert-butyl;

[0113] a halogen atom;

[0114] and m equals 0, 1 or 2, preferably 0 or 1;

[0115] or the residue of a monocyclic or polycyclic hydrocarbon cyclecontaining 5 to 12 carbon atoms carrying the two imine functions in theortho or meta position.

[0116] Preferred bidentate type ligands have formula (Ic₁) in whichgroups R_(a) are identical and represent one of the following groups:

[0117] in which R_(s) represents an alkyl or alkoxy group, preferably C₁to C₄.

[0118] Preferred bidentate ligands have formula (Ic₁) in which 4represents a covalent bond, a methylene or ethylene group, or a divalentcyclic group such as:

[0119] Ligands with formula (Ic₁) are produced by reacting:

[0120] a dicarbonyl compound with formula:

[0121] in which formula (Ic₁), 4 has the meanings given in formula(Ic₁);

[0122] with a primary amine with formula (IIc₂)

R_(a)—NH₂  (IIc₂)

[0123] in which formula (IIc₂), R_(a) has the meanings given in formulae(Ia₁) or (Ia₂).

[0124] Preferred ligands with formula (Ic₂) used in the process of theinvention contain two nitrogen atoms supplied by two imine functions.They preferably result from reacting an α or β carbonylated compound,for example glyoxal, with an amine, preferably cyclohexylamine.

[0125] A preferred example of a ligand is given below:

[0126] Preferred ligands from those cited above are: Chxn-Py-Al,Carbo-Py-Al, Py-Semizone, Chxn-Thio-Al, Py-Alzone and N-Amido-Py-Alzone.

[0127] It should be noted that the ligands used in the process of theinvention can be employed in an optically pure form or in the form of aracemic mixture.

[0128] The different ligands used in the process of the invention areknown products.

[0129] The quantity in which they are used is a function of the quantityof the metallic element M of the catalyst, preferably copper.

[0130] It is generally such that the ratio between the number of molesof ligand and the number of moles of metal is in the range 2 to 1.

[0131] It should be noted that the ligand can be introducedconcomitantly with the compound supplying the catalytic metallicelement. However, the invention also encompasses the case in which ametallic complex is prepared in advance by reacting the compoundsupplying the catalytic metallic element M and the ligand.

[0132] The process of the invention is of importance to a large numberof nucleophilic compounds and examples are given below by way ofillustration which are not limiting in any way.

[0133] A first category of substrates to which the process of theinvention is applicable is formed by organic nitrogen-containingderivatives, more particular primary or secondary amines; hydrazine orhydrazone derivatives; amides; sulphonamides; urea derivatives orheterocyclic derivatives, preferably nitrogen-containing and/orsulphur-containing derivatives.

[0134] More precisely, the primary or secondary amines can berepresented by general formula:

R₁R₂NH  (IIIa)

[0135] in which formula (IIIa):

[0136] R₁, R₂, which may be identical or different, represent a hydrogenatom or have the meanings given for R_(a) and R_(b) in formula (Ia₁) and(Ia2);

[0137] at most one of R₁ and R₂ represents a hydrogen atom.

[0138] Preferred amines have formula (IIIa) in which R₁, R₂, which maybe identical or different, represent a C₁ to C₁₋₅ alkyl group,preferably C₁ to C₁₀, a C₃ to C₈ cycloalkyl group, preferably C₅ or C₆,or a C₆ to C₁₋₂ aryl or arylalkyl group.

[0139] More particular examples of groups R₁ and R₂ that can bementioned are C, to C₄ alkyl groups, phenyl, naphthyl or benzyl groups.

[0140] More specific examples of amines with formula (IIIa) that can bementioned are aniline, N-methylaniline, diphenylamine, benzylamine anddibenzylamine.

[0141] It should be noted that the amino group can be in the form ofanions. The counter-ion is a metal cation, preferably an alkali metalcation, more preferably sodium or potassium. Examples of such compoundsthat can be cited are sodium or potassium amide.

[0142] Other nucleophilic compounds that can be used in the process ofthe invention are hydrazine derivatives with formulae (IIb), (IIIc) or(IIId):

NH₂—NH—COOR₃  (IIIb)

NH₂—NH—COR₄  (IIIc)

NH₂—N═CR₅R₆  (IIId)

[0143] in which formulae (IIb) to (IIId):

[0144] R₃, R_(a), R₅, R₆, which may be identical or different, have themeanings given for R₁ and R₂ in formula (IIIa).

[0145] Groups R₃, R₄, R₅, R₆ more particularly represent a C₁ to C₁₋₅alkyl group, preferably C₁ to C₁₀, a C₃ to C₈ cycloalkyl group,preferably C₅ or C₆, or a C₆ to C₁₋₂ aryl or aryl alkyl group.

[0146] In formulae (IIIb) to (IIId), R₃ preferably represents atertiobutyl group, R₄ represents a methyl or phenyl group and R₅, R₆represent a phenyl group.

[0147] The invention also encompasses amide type compounds, moreparticularly with formula (IIe):

R₇—NH—CO—R₈  (IIIe)

[0148] In which formula (IIIe), R₇ and R₈ have the meanings given for R₁and R₂ in formula (IIIa).

[0149] Examples of compounds with formula (IIIe) that can be cited areoxazolidine-2-one, benzamide and acetamide.

[0150] The invention is also applicable to sulphonamide type compounds.

[0151] They can have the following formula:

R₉—SO₂—NH—R₁₀  (IIIf)

[0152] In which formula (IIIf), R₉ and R₁₀ have the meanings given forR₁ and R₂ in formula (IIIa).

[0153] An example of a compound with formula (IIIf) that can be cited istosylhydrazide.

[0154] Other types of nucleophilic substrates that can be mentioned areurea derivatives such as guanidines which can be represented by formula(IIIg):

[0155] in which formula (IIIg), groups R₁₁, which may be identical ordifferent, have the meanings given for R₁ and R₂ in formula (IIIa).

[0156] An example of a compound with formula (IIIg) that can be cited isN,N,N′,N′-tetramethylguanidine.

[0157] Nucleophilic substrates that are well suited to use in theprocess of the invention are heterocyclic derivatives comprising atleast one nucleophilic atom such as a nitrogen, sulphur or phosphorusatom.

[0158] More precisely, they have general formula (IIIh):

[0159] in which formula (IIIh):

[0160] A represents the residue of a cycle forming all or a portion of amonocyclic or polycyclic, aromatic or non aromatic heterocyclic systemwherein one of the carbon atoms is replaced by at least one nucleophilicatom such as a nitrogen, sulphur or phosphorus atom;

[0161] R₁₂, which may be identical or different, represent substituentson the cycle;

[0162] n represents the number of substituents on the cycle.

[0163] The invention is applicable to monocyclic heterocyclic compoundswith formula (IIIh) in which A represents a saturated or non-saturatedor aromatic heterocycle in particular containing 5 or 6 atoms in thecycle and possibly containing 1 or 3 heteroatoms such as nitrogen,sulphur or oxygen, at least one of which is a nucleophilic atom such asNH or S.

[0164] A can also represent a polycyclic heterocyclic compound definedas being constituted by at least 2 aromatic or non aromatic heterocyclescontaining at least one heteroatom in each cycle and forming ortho- orortho- and pericondensed systems between them, or a group constituted byat least one aromatic or non aromatic carbocycle and at least onearomatic or non aromatic heterocycle forming ortho- or ortho- andperi-condensed systems between them.

[0165] It is also possible to start from a substrate resulting from aconcatenation of a saturated, unsaturated or aromatic heterocycle asdescribed above and a saturated, unsaturated or aromatic carbocycle. Theterm “carbocycle” preferably means a cycloaliphatic or aromatic cyclecontaining 3 to 8 carbon atoms, preferably 6.

[0166] It should be noted that the carbon atoms of the heterocycle canoptionally be substituted with groups R₁₂, either completely orpartially.

[0167] The number of substituents present on the cycle depends on thenumber of atoms in the cycle and on the presence or otherwise ofunsaturated bonds on the cycle.

[0168] The maximum number of substituents that can be carried by thecycle can readily be determined by the skilled person.

[0169] In formula (IIIh), n is a number equal to 4 or less, preferably 0or 1.

[0170] Examples of substituents are given below, but this list is notlimiting in nature.

[0171] Group or groups R₁₂, which may be identical or different,preferably represent one of the following groups:

[0172] a linear or branched C₁ to C₆ alkyl group, preferably C₁ to C₄,such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl ortert-butyl;

[0173] a linear or branched C₂ to C₆ alkenyl or alkynyl group,preferably C₂ to C₄, such as vinyl or allyl;

[0174] a linear or branched C₁ to C₆ alkoxy or thioether group,preferably C₁ to C₄ such as methoxy, ethoxy, propoxy, isopropoxy orbutoxy, or an alkenyloxy group, preferably an allyloxy or phenoxy group;

[0175] a cyclohexyl, phenyl or benzyl group;

[0176] a group or function such as: hydroxyl, thiol, carboxyl, ester,amide, formyl, acyl, aroyl, amide, urea, isocyanate, thioisocyanate,nitrile, nitride, nitro, sulphone, sulphonic, halogen, pseudohalogen ortrifluoromethyl.

[0177] The present invention is particularly applicable to compoundswith formula (IIIh) in which groups R₁₂ more particularly represent analkyl or alkoxy group.

[0178] More particularly, optionally substituted residue A representsone of the following cycles:

[0179] a monocyclic heterocycle containing one or more heteroatoms:

[0180] a bicycle comprising a carbocycle and a heterocycle comprisingone or more heteroatoms;

[0181] a tricycle comprising at least one carbocycle or a heterocyclecomprising one or more heteroatoms;

[0182] Preferred examples of heterocyclic compounds are those withformula (IIIh) in which A represents a cycle such as: imidazole,pyrazole, triazole, pyrazine, oxadiazole, oxazole, tetrazole, indole,pyrole, phthalazine, pyridazine or oxazolidine.

[0183] Nucleophilic compounds that can also be used in the process ofthe invention that can be cited are alcohol or thiol type compoundsrepresented by the following formula:

R₁₃-Z  (IIIi)

[0184] in which formula (IIIi):

[0185] R₁₃ represents a hydrocarbon group containing 1 to 20 atoms andhas the meanings given for R₁ or R₂ in formula (IIIa);

[0186] Z represents a OM₁ or SM₁ type group in which M₁ represents ahydrogen atom or a metallic cation, preferably an alkali metal cation.

[0187] Preferred compounds have formula (IIIi) in which R₁₃ represents ahydrocarbon group containing 1 to 20 carbon atoms, which may be a linearor branched, saturated or unsaturated acyclic aliphatic group; amonocyclic or polycyclic, saturated, unsaturated or aromatic carbocyclicor heterocyclic group; or a concatenation of said groups.

[0188] More precisely, R₁₃ preferably represents a linear or branchedsaturated acyclic aliphatic group preferably containing 1 to 12 carbonatoms, more preferably 1 to 4 carbon atoms.

[0189] The invention also encompasses the presence of an unsaturatedbond in the hydrocarbon chain such as one or more double bonds, whichmay or may not be conjugated, or a triple bond.

[0190] As mentioned for R_(a) defined in formula (Ia₁) or (Ia₂), thehydrocarbon chain can optionally be interrupted by a heteroatom or afunctional group, or it may carry one or more substituents.

[0191] In formula (IIIi), R₁₃ can also represent a saturated or nonsaturated carbocyclic group, preferably containing 5 or 6 carbon atomsin the cycle; a saturated or non saturated heterocyclic group,containing 5 or 6 carbon atoms in the cycle including 1 or 2 heteroatomssuch as nitrogen, sulphur, oxygen or phosphorus atoms; a monocyclic,aromatic heterocyclic carbocyclic group, preferably phenyl, pyridyl,furyl, pyrannyl, thiophenyl, thienyl, phospholyl, pyrazolyl, imidazolylor pyrolyl, or a polycyclic, aromatic heterocyclic carbocyclic groupwhich may or may not be condensed, preferably naphthyl.

[0192] When R₁₃ includes a cycle, it can also be substituted. The natureof the substituent is unimportant provided that it does not interferewith the principal reaction. The number of substituents is generally atmost 4 per cycle, usually 1 or 2. Reference should be made to thedefinition of R₁₂ in formula (IIIh).

[0193] The invention also encompasses the case in which R₁₃ comprises aconcatenation of aliphatic and/or cyclic, carbocyclic and/orheterocyclic groups.

[0194] One acyclic aliphatic group may be connected to a cycle via acovalent bond, a heteroatom or a functional group such as oxy, carbonyl,carboxy, sulphonyl, etc. . . . .

[0195] More particular groups are cycloalkylalkyl, for examplecyclohexylalkyl, or aralkyl groups containing 7 to 12 carbon atoms, inparticular benzyl or phenylethyl.

[0196] The invention also encompasses a concatenation of carbocyclicand/or heterocyclic groups, more particularly a concatenation of phenylgroups separated by a covalent bond or an atom or a functional group Gsuch as: oxygen, sulphur, sulpho, sulphonyl, carbonyl, carbonyloxy,imino, carbonylimino, hydrazo or alkylene (C₁-C₁₀, preferablyC₁)-diimino.

[0197] The linear or branched, saturated or unsaturated acyclicaliphatic group can optionally carry a cyclic substituent. The term“cycle” means a saturated, unsaturated or aromatic carbocyclic orheterocyclic cycle.

[0198] Preferred compounds with formula (IIIi) have general formula(IIIi₁):

[0199] in which:

[0200] B represents the residue of a monocyclic or polycyclic, aromatic,carbocyclic group or a divalent group constituted by a concatenation oftwo or more monocyclic aromatic carbocyclic groups;

[0201] R₁₄ represents one or more substituents, which may be identicalor different;

[0202] Z represents an OM₁ or SM₁ group in which M₁ represents ahydrogen atom or a metallic cation, preferably an alkali metal cation;

[0203] n+ is 5 or less.

[0204] Examples of substituents R₁₄ can be found by referring to thosefor R₁₂ defined for formula (IIIh).

[0205] More particular compounds with formula (IIIi₁) are those in whichresidue (B) represents:

[0206] a monocyclic or polycyclic aromatic carbocyclic group with cyclesthat can together form an ortho-condensed system with formula (F₄):

[0207] in which formula (F₄), m represents 0, 1 or 2 and symbols R₁₄ andn′, which may be identical or different, have the meanings given above;

[0208] a group constituted by a concatenation of two or more monocyclicaromatic carbocyclic groups with formula (F₅):

[0209] in which formula (F₅), symbols R₁₄ and n′, which may be identicalor different, have the meanings given above, p is 0, 1, 2 or 3 and wrepresents a covalent bond, an alkylene or alkylidene C₁ to C₄ group,preferably a methylene group or isopropylidene group, or a functionalgroup such as G.

[0210] Preferred compounds with formula (IIIi) have formulae (F₄) and(F₅) in which:

[0211] R₁₄ represents a hydrogen atom, a hydroxyl group, a —CHO group, a—NO₂ group, or a linear or branched alkyl or alkoxy group containing 1to 6 carbon atoms, preferably 1 to 4 carbon atoms, more preferablymethyl, ethyl, methoxy or ethoxy;

[0212] w represents a covalent bond, an alkylene or alkylidene groupcontaining 1 to 4 carbon atoms or an oxygen atom;

[0213] m is 0 or 1;

[0214] n′ is O, 1 or 2;

[0215] p is 0 or 1.

[0216] Illustrative examples of compounds with formula (IIIi) that canin particular be mentioned are:

[0217] those in which residue B has formula (F₄) in which m and n′ equal0, such as phenol or thiophenol;

[0218] those in which residue B has formula (F₄) in which n′ equals 0and n′ equals 1, such as hydroquinone, pyrocatechine, resorcin,alkylphenols, alkylthiophenols, alkoxyphenols, salicylic aldehyde,p-hydroxybenzaldehyde, methyl salicylate, p-hydroxybenzoic acid methylester, chlorophenols, nitrophenols or p-acetamidophenol;

[0219] those in which residue B has formula (F₄) in which m equals 0 andn′ equals 2, such as dialkylphenols, vanillin, isovanillin,2-hydroxy-5-acetamidobenzaldehyde, 2-hydroxy-5-propionamidobenzaldehyde,4-allyloxybenzaldehyde, dichlorophenols, methylhydroquinone orchlorohydroquinone;

[0220] those in which residue B has formula (F₄) in which m equals 0 andn′ equals 3, such as 4-bromovanillin, 4-hydroxyvanillin,trialkylphenols, 2,4,6-trinitrophenol, 2,6-dichloro-4-nitrophenol,trichlorophenols, dichlorohydroquinones or 3,5-dimethoxy-4-benzaldehyde;

[0221] those in which residue B has formula (F₄) in which m equals 1 andn′ is I or more, such as dihydroxynaphthalene, 4-methoxy-1-naphthol or6-bromo-2-naphthol;

[0222] those in which residue B has formula (F₅) in which p is I and n′is 1 or more, such as 2-phenoxyphenol, 3-phenoxyphenol,phenylhydroquinone, 4,4′-dihydroxybiphenyl, isopropylidene 4,4′-diphenol(bisphenol A), bis(4-hydroxyphenyl)methane,bis(4-hydroxyphenyl)sulphone, bis(4-hydroxyphenyl)sulphoxide ortetrabromo bisphenol A.

[0223] Other nucleophilic compounds that can be used in the process ofthe invention are hydrocarbon derivatives containing a nucleophiliccarbon.

[0224] More particular examples are malonate type anions comprising a—OOC—HC⁻—COO— group.

[0225] Alkyl malonate anions with formula (IIIj) can be mentioned:

R₁₅—OOC—HC⁻—COO—R₁₅,  (IIIj)

[0226] in which formula (IIIj), R₁₅ and R₁₅′, which may be identical ordifferent, represent an alkyl group containing 1 to 12 atoms in thealkyl group, preferably 1 to 4 atoms.

[0227] It is also possible to cite malodinitrile type anions containinga NC—HC⁻—CN group.

[0228] It is also possible to use nitrile type compounds represented byformula (IIIk):

R₁₆—CN  (IIIk)

[0229] in which formula R₁₆ has any nature and has the meanings givenfor R₁ and also represents a metallic cation, preferably an alkalication, more preferably lithium, sodium or potassium.

[0230] R₁₆ has the meanings given for R_(1.)

[0231] Examples of nitrites that can be mentioned are acetonitrile,cyanobenzene optionally carrying one or more substituents on the benzenering, or ethanal cyanhydrine CH₃CH(OH)CN.

[0232] It is also possible to use acetylenide type compounds in theprocess of the invention.

[0233] They can be represented by the formula (IIIm):

R₁₇—C≡⁻  (IIIm)

[0234] in which formula R₁₇ is of any nature and the counter-ion is ametal cation, preferably a sodium or potassium atom.

[0235] R₁₇ has the meanings given for R₁.

[0236] Particular examples that can be cited are sodium or potassiumacetylide or diacetylide.

[0237] Other classes of nucleophilic compounds that can be employed inthe process of the invention that can be cited are profene typecompounds and their derivatives represented by the following formula:

R₁₈—HC⁻—COO—R₁₉  (IIIn)

[0238] in which formula:

[0239] R₁₈ has the meanings given for R₁;

[0240] R₁₉ represents an alkyl group containing 1 to 12 atoms in thealkyl group, preferably 1 to 4 atoms.

[0241] Preferred compounds are those with formula (IIIn) in which R₁₈represents an alkyl group containing 1 to 12 carbon atoms, a cycloalkylgroup containing 5 or 6 carbon atoms and an aryl group containing 6 or12 carbon atoms or a nitrogen-containing heterocycle containing 5 or 6atoms.

[0242] A further category of nucleophiles that can be used in theprocess of the invention is formed by amino acids and their derivatives:

[0243] in which formula:

[0244] R_(AA) represents the residue of an amino acid, preferably ahydrogen atom, a linear or branched C₁ to C₁₂ alkyl group optionallycarrying a functional group, an aryl group or an arylalkyl C₆ to C₁₂group or a functional group, preferably a hydroxyl group;

[0245] R₂₀ and R₂₁ have the meanings given for R₁ and R₂ in formula(IIIa);

[0246] R_(h) represents a hydrogen atom, a metal cation, preferably analkali metal cation or a hydrocarbon group containing 1 to 12 carbonatoms, preferably a C₁ to C₁₂ alkyl group.

[0247] In formula (IIIo), R_(AA) represents an alkyl group that cancarry a functional group, examples of which that can be cited being an—OH, —NH₂, —CO—NH₂, —NH—CNH—, —HN—C(O)—NH₂—, —COOH, —SH, —S—CH₃ group oran imidazole, pyrole or pyrazole group.

[0248] Examples of amino acids that can be cited are glycine, cysteine,aspartic acid, glutamic acid and histidine.

[0249] Examples of nucleophilic compounds of any other nature that canbe mentioned are phosphorus or phosphorus- and nitrogen-containingcompounds, more particularly those with the following formulae:

[0250] phosphides with formula

(R₂₂)₂—P⁻  (IIIp)

[0251] phosphines with formula

(R₂₂)₃—P⁻  (IIIq)

[0252] phosphonium diazoylides with formula

(R₂₂)₃—P⁺—N²  (IIIr)

[0253] phosphonium azoylides with formula

(R₂₂)₃—P⁺—N⁻R₂₃  (IIIs)

[0254] in which formulae (IIIp) to (IIIs), groups R₂₂, which may beidentical or different, and group R₂₃ represent:

[0255] an alkyl group containing 1 to 12 carbon atoms;

[0256] a cycloalkyl group containing 5 or 6 carbon atoms;

[0257] a cycloalkyl group containing 5 or 6 carbon atoms, substitutedwith one or more alkyl radicals containing 1 to 4 carbon atoms, oralkoxy radicals containing 1 or 4 carbon atoms;

[0258] a phenylalkyl group the aliphatic portion of which contains 1 to6 carbon atoms;

[0259] a phenyl group;

[0260] a phenyl group substituted with one or more alkyl radicalscontaining 1 to 4 carbon atoms or alkoxy containing 1 to 4 carbon atomsor one or more halogen atoms.

[0261] More particular examples of phosphorus-containing compounds thatcan be cited are tricyclohexylphosphine, trimethylphosphine,triethylphosphine, tri-n-butylphosphine, triisobutylphosphine,tri-tert-butylphosphine, tribenzylphosphine,dicyclohexylphenylphosphine, triphenylphosphine,dimethylphenylphosphine, diethylphenylphosphine anddi-tert-butylphenylphosphine.

[0262] Other nucleophilic compounds that can be used include boronicacids or their derivatives, more particularly those with the followingformula:

[0263] in which:

[0264] R₂₄ represents a monocyclic or polycyclic, aromatic, carbocyclicor heterocyclic group;

[0265] Q₁, Q₂, which may be identical or different, represent a hydrogenatom, a linear or branched, saturated or unsaturated aliphatic groupcontaining 1 to 20 carbon atoms, or a R₂₄ group.

[0266] More precisely, the boronic acid has formula (IIIt) in whichgroup R₂₄ represents an aromatic carbocyclic or heterocylic group. R₂₄can have the meanings given above for B in formula (IIIi₁). However, R₂₄more particularly represents a carbocyclic group such as a phenyl,naphthyl or heterocyclic group such as a pyrrolyl, pyridyl, pyrimidyl,pyridazinyl, pyrazinyl, 1,3-thiazolyl, 1,3,4-thiadiazolyl or a thienylgroup.

[0267] The aromatic cycle can also be substituted. The number ofsubstituents is generally at most 4 per cycle, but usually it is 1 or 2.Reference should be made to the definition of R₁₂ in formula (IIIh) forexamples of substituents.

[0268] Preferred substituents are alkyl or alkoxy groups containing 1 to4 carbon atoms, an amino group, a nitro group, a cyano group, a halogenatom or a trifluoromethyl group.

[0269] Q₁, Q₂, which may be identical or different, more particularlyrepresent a hydrogen atom, or a linear or branched acyclic aliphaticgroup containing 1 to 20 carbon atoms which may be saturated or containone or more unsaturated bonds in the chain, preferably 1 to 3unsaturated bonds, preferably simple or conjugated double bonds.

[0270] Q₁, Q₂, preferably represent an alkyl group containing 1 to 10carbon atoms, preferably 1 to 4, or an alkenyl group containing 2 to 10carbon atoms, preferably a vinyl or a 1-methylvinyl group.

[0271] Q₁, Q₂, can have the meanings given for R₂₄; in particular, anycycle can also carry a substituent as described above.

[0272] Preferably, R₂₄ represents a phenyl group.

[0273] The scope of the present invention encompasses derivatives ofboronic acids such as anhydrides and esters, more particularly alkylesters containing 1 to 4 carbon atoms.

[0274] Particular examples of arylboronic acids that can be cited are:benzeneboronic acid, 2-thiopheneboronic acid; 3-thiopheneboronic acid;4-methylbenzeneboronic acid, 3-methylthiophene-2-boronic acid,3-aminobenzeneboronic acid, 3-aminobenzeneboronic acid hemisulphate,3-fluorobenzeneboronic acid, 4-fluorobenzeneboronic acid,2-formylbenzeneboronic acid, 3-formylbenzeneboronic acid,4-formylbenzeneboronic acid, 2-methoxybenzeneboronic acid,3-methoxybenzeneboronic acid, 4-methoxybenzeneboronic acid,4-chlorobenzeneboronic acid, 5-chlorothiophene-2-boronic acid,benzo[b]furan-2-boronic acid, 4-carboxybenzeneboronic acid,2,4,6-trimethylbenzeneboronic acid, 3-nitrobenzeneboronic acid,4-(methylthio)benzeneboronic acid, 1-naphthaleneboronic acid,2-naphthaleneboronic acid, 2-methoxy-1-naphthaleneboronic acid,3-chloro-4-fluorobenzeneboronic acid, 3-acetamidobenzeneboronic acid,3-trifluoromethylbenzeneboronic acid, 4-trifluoromethylbenzeneboronicacid, 2,4-dichlorobenzeneboronic acid, 3,5-dichlorobenzeneboronic acid,3,5-bis(trifluoromethyl)benzeneboronic acid, 4,4′-biphenyldiboronicacid, and esters and anhydrides of said acids.

[0275] The present text provides lists of nucleophilic compounds thatare in no way limiting and any type of nucleophilic compound can beenvisaged.

[0276] In accordance with the process of the invention, a —C—C or—C—Nu—(O,S,P,N,Si, B . . . ) bond can be created by reacting anucleophilic compound with a compound comprising an unsaturated bond inthe position α to a leaving group.

[0277] More precisely, it is a compound comprising a leaving group Yrepresented by the formula (IV):

R₀—Y  (IV)

[0278] in which formula R₀ represents a hydrocarbon group containing 2to 20 carbon atoms and has a double bond or a triple bond located in theposition α to a leaving group Y, or a monocyclic or polycyclic,aromatic, carbocyclic and/or heterocyclic group.

[0279] In accordance with the process of the invention, the compoundwith formula (III) is reacted with a compound with formula (IV) inwhich:

[0280] R₀ represents an aliphatic hydrocarbon group containing a doublebond or a triple bond in the position α to the leaving group or a cyclichydrocarbon group containing an unsaturated bond carrying a leavinggroup;

[0281] R₀ represents a monocyclic or polycyclic, aromatic, carbocyclicand/or heterocyclic group;

[0282] Y represents a leaving group, preferably a halogen atom, or asulphonic ester group with formula —OSO₂—R_(c), in which R_(e) is ahydrocarbon group.

[0283] The compound with formula (IV) will henceforth be designated as a“compound carrying a leaving group”.

[0284] In the formula for the sulphonic ester group, R_(e) is ahydrocarbon group of any nature. However, given that Y is a leavinggroup, it is advantageous from an economic viewpoint for R_(e) to besimple in nature, and more particularly to represent a linear orbranched alkyl group containing 1 to 4 carbon atoms, preferably a methylor ethyl group, but it can also represent a phenyl or tolyl group or atrifluoromethyl group, for example. The preferred group Y is a triflategroup, which corresponds to a group R_(e) representing a trifluoromethylgroup.

[0285] Bromine or chlorine atoms constitute preferred leaving groups.

[0286] More particularly, compounds with formula (IV) used in accordancewith the process of the invention can be classified into three groups:

[0287] (1) aliphatic type compounds, carrying a double bond which can berepresented by formula (IVa):

[0288] in which formula (IVa):

[0289] R₂₅, R₂₆ and R₂₇, which may be identical or different, representa hydrogen atom or a hydrocarbon group containing 1 to 20 carbon atoms,which can be a linear or branched, saturated or unsaturated aliphaticgroup; a monocyclic or polycyclic, saturated, unsaturated or aromaticcarbocyclic or heterocyclic group; or a concatenation of aliphaticand/or carbocyclic and/or heterocyclic groups as defined above;

[0290] Y represents the leaving group, as defined above;

[0291] (2) aliphatic type compounds, carrying a triple bond, representedby formula (IVb):

[0292] in which formula (IVb):

[0293] R₂₅ has the meaning given in formula (IVa);

[0294] Y represents a leaving group as defined above;

[0295] (3) aromatic type compounds, hereinafter designated as a“halogenoaromatic compound” and which can be represented by formula(IVc):

R₂₅—C≡C—Y  (IVb)

[0296] in which:

[0297] D represents the residue of a cycle forming all or a portion of amonocyclic or polycyclic, aromatic, carbocyclic and/or heterocyclicsystem;

[0298] R₂₈, which may be identical or different, represent substituentson the cycle;

[0299] Y represents a leaving group as defined above;

[0300] n″ represents the number of substituents on the cycle.

[0301] The invention is applicable to unsaturated compounds withformulae (IVa) and (IVb) in which R₂₅ preferably represents a saturatedlinear or branched acyclic aliphatic group preferably containing 1 to 12carbon atoms.

[0302] The invention does not exclude the presence of a furtherunsaturated bond on the hydrocarbon chain, such as a further triple bondor one or more double bonds, which may or may not be conjugated.

[0303] The hydrocarbon chain can optionally be interrupted by aheteroatom (for example oxygen or sulphur) or by a functional groupprovided that it does not react; in particular, a group such as —CO— canbe cited.

[0304] The hydrocarbon chain can optionally carry one or moresubstituents provided that they do not react under the reactionconditions; particular mention can be made of a halogen atom, a nitrilegroup or a trifluoromethyl group.

[0305] The linear or branched, saturated or unsaturated acyclicaliphatic group can optionally carry a cyclic substituent. The term“cycle” means a saturated, unsaturated or aromatic, carbocyclic orheterocyclic cycle.

[0306] The acyclic aliphatic group can be connected to the cycle via acovalent bond, a heteroatom or a functional group such as oxy, carbonyl,carboxy, sulphonyl, etc. . . . .

[0307] Examples of cyclic substituents that can be envisaged arecycloaliphatic, aromatic or heterocyclic substituents, in particularcycloaliphatic, containing 6 carbon atoms in the cycle, or benzenic,said cyclic substituents themselves optionally carrying any substituentprovided that they do not interfere with the reactions occurring in theprocess of the invention. Particular mention can be made of alkyl oralkoxy groups containing 1 to 4 carbon atoms.

[0308] More particular examples of aliphatic groups carrying a cyclicsubstituent are aralkyl groups containing 7 to 12 carbon atoms, inparticular benzyl or phenylethyl.

[0309] In formulae (IVa) and (IVb), R₂₅ can also represent a carbocyclicgroup that may or may not be saturated, preferably containing 5 or 6carbon atoms in the cycle, preferably cyclohexyl; a heterocyclic group,which may or may not be saturated, in particular containing 5 or 6carbon atoms in the cycle 1 or 2 of which are heteroatoms such asnitrogen, sulphur or oxygen; a monocyclic aromatic carbocyclic group,preferably phenyl, or a polycyclic aromatic carbocyclic group, which mayor may not be condensed, preferably naphthyl.

[0310] Regarding R₂₆ and R₂₇, they preferably represent a hydrogen atomor an alkyl group containing 1 to 12 carbon atoms, or a phenyl group oran aralkyl group containing 7 to 12 carbon atoms, preferably a benzylgroup.

[0311] In formulae (IVa) and/or (IVb), R₂₅, R₂₆ and R₂₇ moreparticularly represent a hydrogen atom or R₂₅ represents a phenyl groupand R₂₆, R₂₇ represent a hydrogen atom.

[0312] Examples of compounds with formulae (IVa) and (IVb) that can becited are vinyl chloride or bromide, β-bromo- or β-chlorostyrene orbromoalkyne or iodoalkyne.

[0313] The invention is of particular application to halogenoaromaticcompounds with formula (IVc) in which D is the residue of a cycliccompound, preferably containing at least 4 carbon atoms in its cycle,preferably 5 or 6, optionally substituted, and representing at least oneof the following cycles:

[0314] a monocyclic or polycyclic aromatic carbocycle, i.e., a compoundconstituted by at least 2 aromatic carbocycles and between them formingortho- or ortho- and peri-condensed systems, or a compound constitutedby at least 2 carbocycles only one of which is aromatic and between themforming ortho- or ortho- and peri-condensed systems;

[0315] a monocyclic aromatic heterocycle containing at least one ofheteroatoms P, O, N or S or a polycyclic aromatic heterocycle, i.e., acompound constituted by at least 2 heterocycles containing at least oneheteroatom in each cycle wherein at least one of the two cycles isaromatic and between them forming ortho- or ortho- and peri-condensedsystems, or a compound constituted by at least one carbocycle and atleast one heterocycle at least one of the cycles being aromatic andforming ortho- or ortho- and peri-condensed systems between them.

[0316] More particularly, optionally substituted residue D preferablyrepresents the residue of an aromatic carbocycle such as benzene, anaromatic bicycle containing two aromatic carbocycles such asnaphthalene; or a partially aromatic bicycle containing two carbocyclesone of which is aromatic, such as tetrahydro-1,2,3,4-naphthalene.

[0317] The invention also envisages the fact that D can represent theresidue of a heterocycle provided that it is more electrophilic than thecompound with formula (IIIh).

[0318] Particular examples that can be cited are an aromatic heterocyclesuch as furan or pyridine; an aromatic bicycle comprising an aromaticcarbocycle and an aromatic heterocycle such as benzofuran orbenzopyridine; a partially aromatic bicycle comprising an aromaticcarbocycle and a heterocycle such as methylenedioxybenzene; an aromaticbicycle comprising two aromatic heterocycles such as1,8-naphthylpyridine; a partially aromatic bicycle comprising acarbocycle and an aromatic heterocycle such as5,6,7,8-tetrahydroquinoline.

[0319] In the process of the invention, a halogenoaromatic compound withformula (IVc) is preferably used in which D represents an aromaticnucleus, preferably a benzene or naphthalene nucleus.

[0320] The aromatic compound with formula (IVc) can carry one or moresubstituents.

[0321] In the present text, the term “several” generally means less than4 substituents R₂₈ on the aromatic nucleus.

[0322] Reference should be made to the definitions of R₁₂ in formula(IIIH) for examples of substituents.

[0323] In formula (IVc), n″ is a number that is 4 or less, preferably 1or 2.

[0324] Examples of compounds with formula (IVc) that can be cited arep-chlorotoluene, p-bromoanisole and p-bromotrifluorobenzene.

[0325] The quantity of compound carrying a leaving group with formula(IV), preferably with formula (IVa) or (IVb) or (IVc), is generallyexpressed with respect to the quantity of nucleophilic compound and isclose to stoichiometry. The ratio between the number of moles ofcompound carrying a leaving group and the number of moles ofnucleophilic compound is usually in the range 0.9 to 1.2.

[0326] In accordance with the process of the invention, the nucleophiliccompound preferably with formulae (IIIa) to (IIIt) is reacted with acompound carrying a leaving group with formula (IV), preferably withformula (IVa) or (IVb) or (IVc), in the presence of an effectivequantity of a catalyst based on a metallic element M selected from group(VIII), (Ib) and (IIb) and a ligand as defined in the invention.

[0327] In the present text, reference will be made below to the periodictable published in the Bulletin de la Société Chimique de France, n° 1(2366).

[0328] The different metals M can be used as a mixture, in particular asa mixture with copper.

[0329] Examples of metals M that can be cited are copper, silver,palladium, cobalt, nickel, iron and/or zinc.

[0330] When a single metal M is used, copper or palladium is preferablyselected.

[0331] Examples of catalysts that can be used that can be cited arecopper metal or organic or inorganic compounds of copper (I) or copper(II).

[0332] The catalysts employed in the process of the invention are knownproducts.

[0333] Examples of copper catalysts of the invention that can be citedare cuprous bromide, cupric bromide, cuprous iodide, cupric iodide,cupric chloride, basic copper (II) carbonate, cuprous nitrate, cupricnitrate, cuprous sulphate, cupric sulphate, cuprous sulphite, cuprousoxide, cuprous acetate, cupric acetate, cuprictrifluoromethylsulphonate, cupric hydroxide, copper (I) methylate,copper (II) methyate and chlorocupric methylate with formula ClCuOCH₃.

[0334] A palladium catalyst is used in the process of the invention. Thepalladium can be supplied in the form of a finely divided metal or inthe form of an inorganic derivative such as an oxide or hydroxide. It ispossible to use a mineral salt, preferably a nitrate, sulphate,oxysulphate, halide, oxyhalide, silicate, carbonate, or an organicderivative, preferably the cyanide, oxalate or acetylacetonate; analcoholate, more preferably methylate or ethylate; or a carboxylate,still more preferably the acetate. It is also possible to use complexes,in particular chlorine-containing or cyanide containing complexes withpalladium and/or alkali metals, preferably sodium, potassium orammonium.

[0335] Examples of compounds that can be used to prepare the catalystsof the invention that can be cited are palladium (II) bromide, palladium(II) chloride, palladium (II) iodide, palladium (II) cyanide, hydratedpalladium (II) nitrate, palladium (II) oxide, dihydrated palladium (II)sulphate, palladium (II) acetate, palladium (II) propionate, palladium(II) butyrate, palladium (II) benzoate, palladium (II) acetylacetonate,ammonium tetrachloropalladate (II), potassium hexachloropalladate (IV),palladium (II) tetramine nitrate, palladium (II)dichlorobis(acetonitrile), palladium (II) dichlorobis(benzonitrile),palladium (II) dichloro(1,5-cyclooctadiene), palladium (II)dichlorodiamine, palladium (0) tetrakistriphenylphosphine, palladium(II) acetate and trisbenzylideneacetone palladium (0).

[0336] Specific examples of nickel derivatives that can be cited arenickel (II) halides such as nickel (II) chloride, bromide or iodide;nickel (II) sulphate; nickel (II) carbonate; salts of organic acidscontaining 1 to 18 carbon atoms, in particular the acetate orpropionate; nickel (II) complexes such as nickel (II) acetylacetonate,nickel (II) dibromo-bis-(triphenylphosphine), nickel (II)dibromo-bis(pyridine); or nickel (O) complexes such as nickel (O)bis-(cycloocta-1,5-diene) or nickel (O) bis-diphenylphosphinoethane.

[0337] It is also possible to use catalysts based on iron or zinc,generally in the form of the oxide, hydroxide or salts such as halides,preferably the chloride, nitrate or sulphate.

[0338] Preferably, cupric chloride or bromide and cuprous oxide areselected.

[0339] The quantity of catalyst used, expressed as the mole ratiobetween the number of moles of catalyst and the number of moles ofcompound with formula (IV), is generally in the range 0.01 to 0.1.

[0340] A base, the function of which is to trap the leaving group, isalso used in the process of the invention.

[0341] The feature of the base is that it has a pKa of 2 or more,preferably in the range 4 to 30.

[0342] The pKa is defined as the ionic dissociation constant of theacid/base pair when water is used as the solvent.

[0343] Reference should be made, inter alia, to the “Handbook ofChemistry and Physics”, 66^(th) edition, p. D-161 and D-162 in order toselect a base with a suitable pKa.

[0344] Suitable bases that can be cited include mineral bases such asalkali metal carbonates, bicarbonates or hydroxides, preferably ofsodium, potassium, caesium or alkaline-earth metals, preferably calcium,barium or magnesium.

[0345] It is also possible to use alkali metal hydrides, preferablysodium hydride or alkali metal alcoholates, preferably of sodium orpotassium, more preferably sodium methylate, ethylate or tertiobutylate.

[0346] It is also possible to use organic bases as tertiary amines, moreparticularly triethylamine, tri-n-propylamine, tri-n-butylamine,methyldibutylamine, methyldicyclohexylamine, ethyldiisopropylamine,N,N-diethylcyclohexylamine, pyridine, dimethylamino-4-pyridine,N-methylpiperidine, N-ethylpiperidine, N-n-butylpiperidine,1,2-methylpiperidine, N-methylpyrrolidine and 1,2-dimethylpyrrolidine.

[0347] Preferred bases are alkali metal carbonates.

[0348] The quantity of base employed is such that the ratio between thenumber of moles of base and the number of moles of aromatic compoundcarrying the leaving group is preferably in the range 1 to 4.

[0349] The arylation or vinylation or alkynylation reaction of theinvention is usually carried out in the presence of an organic solvent.

[0350] An organic solvent is used that does not react under the reactionconditions.

[0351] The type of solvent used is preferably a polar organic solvent,more preferably aprotic:

[0352] linear or cyclic carboxamides such as N,N-dimethylacetamide(DMAC), N,N-diethylacetamide, dimethylformamide (DMF), diethylformamideor 1-methyl-2-pyrrolidinone IMP);

[0353] dimethylsulphoxide (DMSO);

[0354] hexamethylphosphotriamide (HMPT);

[0355] tetramethyurea;

[0356] nitro compounds such as nitromethane, nitroethane,1-nitropropane, 2-nitropropane or mixtures thereof, and nitrobenzene;

[0357] aliphatic or aromatic nitrites such as acetonitrile,propionitrile, butanenitrile, isobutanenitrile, pentanenitrile,2-methylglutaronitrile or adiponitrile;

[0358] tetramethylene sulphone (sulpholane);

[0359] organic carbonates such as dimethylcarbonate,diusopropylcarbonate or di-n-butylcarbonate;

[0360] alkyl esters such as ethyl or isopropyl acetate;

[0361] halogenated or non halogenated aromatic hydrocarbons such aschlorobenzene or toluene;

[0362] ketones, such as acetone, methylethylketone,methylisobutylketone, cyclopentanone, cyclohexanone;

[0363] nitrogen-containing heterocycles such as pyridine, picoline andquinolines.

[0364] It is also possible to use a mixture of solvents.

[0365] The quantity of organic solvent to be used is determined as afunction of the nature of the selected organic solvent.

[0366] It is determined so that the concentration of the compoundcarrying a leaving group in the organic solvent is preferably in therange 5% to 40% by weight.

[0367] The arylation or vinylation or alkynylation reaction of thenucleophilic compound takes place at a temperature that isadvantageously in the range 0° C. to 120° C., preferably in the range20° C. to 100° C., more preferably in the range 25° C. to 85° C.

[0368] The arylation or vinylation or alkynylation reaction is generallycarried out at atmospheric pressure, but higher pressures of up to 10bars, for example, can also be used.

[0369] In practice, the reaction is simple to carry out.

[0370] The order of using the reagents is not critical. Preferably, the(preferably copper) catalyst, the ligand, the nucleophilic compound withformula (III), the base, the compound carrying a leaving group withformula (IV) and the organic solvent are charged.

[0371] The reaction medium is heated to the desired temperature.

[0372] The progress of the reaction is monitored by following thedisappearance of the compound carrying a leaving group.

[0373] At the end of the reaction, a product of the type R—Nu—R₀ isobtained, more particularly an arylated compound comprising the residueof the nucleophilic compound and the residue of an electrophiliccompound preferably with the following formula (V):

[0374] in which formula (V), D, R, R₂₉, Nu and n″ have the meaningsgiven above.

[0375] The compound obtained is recovered using conventional techniques,in particular by crystallisation from an organic solvent.

[0376] More specific examples of organic solvents that can be mentionedare aliphatic or aromatic, halogenated or non halogenated hydrocarbons,carboxamides and nitrites. Particular mention can be made ofcyclohexane, toluene, dimethylformamide and acetonitrile.

[0377] Examples of the invention will now be given. These examples aregiven by way of illustration and are not limiting in nature.

[0378] Before describing the examples, we shall describe the operatingprotocol used in all of the examples unless otherwise indicated. Thepreparation of certain ligands and catalysts is also illustrated.

[0379] In the examples, the degree of transformation (TT) corresponds tothe ratio between the number of moles of substrate transformed and thenumber of moles of substrate engaged.

[0380] The yield (RR) corresponds to the ratio between the number ofmoles of product formed and the number of moles of substrate engaged.

[0381] The transformation yield (RT) or selectivity corresponds to theratio between the number of moles of product formed and the number ofmoles of substrate engaged.

EXAMPLES Operating Protocol

[0382] The following are successively introduced into a 35 ml Schlenktube placed in a nitrogen atmosphere:

[0383] copper catalyst (0.05 mmoles);

[0384] ligand (0.1 mmoles);

[0385] nucleophilic compound (0.75 mmoles);

[0386] a base (1 mmoles);

[0387] 56 μl of iodobenzene (0.5 mmoles);

[0388] and 300 μl of acetonitrile.

[0389] The mixture is placed in an oil bath at a temperature of 50° C.and stirred for 90 hours.

[0390] After this period, the mixture is diluted with ethyl ether ordichloromethane.

[0391] 65 μl of internal reference (1,3-dimethoxybenzene) is introducedand a sample of reaction medium is removed then filtered over celite (orfilter medium) eluting with ethyl ether or dichloromethane depending onthe solubility.

[0392] The arylated compound obtained is extracted with ethyl ether ordichloromethane, then with distilled water and the product obtained isanalysed by gas chromatography using 1,3-dimethoxybenzene as an internalreference.

[0393] Preparation of Ligands:

[0394] a Preparation of trans-1,2-bis(2′-pyridylidenamino)-cyclohexane(Chxn-Py-Al) With Formula:

[0395] The ligand was prepared using the method described by Gao. H—X;Zhang, H.; Yi, X-D; Xu, P.-P.; Tang, C.-L.; Wan, H.-L.; Tsai, K.-R.;Ikariya, T.; (Chirality 2000, 12, 383-388).

[0396] 12.65 g of anhydrous magnesium sulphate (105.1 mmoles) and 4.2 mlof a racemic trans-1,2-diaminocyclohexane mixture (35.0 mmoles) weresuccessively added to a solution of 6.66 ml of 2-pyridylaldehyde (70.0mmoles) in 50 ml of absolute ethanol.

[0397] The reaction mixture was stirred for 20 hours at ambienttemperature (the solution turned yellow after stirring for three hours),heated for 2.5 hours under reflux, then filtered through a frit.

[0398] The isolated solid was washed with dichloromethane.

[0399] The total filtrate was concentrated completely under reducedpressure to isolate an ochre solid, which was re-crystallised fromethanol.

[0400] 8.2 g of pale yellow crystals were obtained, which correspondedto a 80.1% yield.

[0401] The characteristics were as follows:

[0402] M.Pt: 140-141° C. (EtOH) (racemic mixture) (Lit: 127-129° C.:obtained by Belokon, Y N; North, M: Churkina, T D; Ikonnikov, N S;Maleev, V I; Tetrahedron 2001, 57, 2491-2498 for the stereoisomer 1S,2S,hexane-MeOH);

[0403]¹H NMR/CDCl₃: δ 8.51 (m, 2H, H_(1,2)), 8.28 (s, 2H, H_(7,14)),7.84 (m, 2H, H_(4,17)), 6.55-7.64 (m, 2H, H_(5,16)), 7.14-7.21 (m, 2H,H_(3,18)), 3.50 (m, 2H, H₈, 13), 1,81 (m, 6H, H_(10,11) and H carried bycarbons 9 and 12 located in the position cis (or trans) with respect tothe adjacent nitrogen atoms), 1.40-1.53 (m, 2H, H carried by carbons 9and 12 located in the trans (or cis) position with respect to theadjacent nitrogen atoms).

[0404]¹³C NMR/CDCl₃: δ 161.42 (C7 and C14), 154.61 (C6 to C15), 149.21(C1 and C2), 136.39 (C4 and C17), 124.43 (C3 and C18), 121.29 (C5 andC16), 73.53 (C8 and C13), 32.70 (C9 and C12), 24.33 (C10 and C11).

[0405] FAB+ (NBA matrix): 293 (100%, M+1), 107 (52%,2-pyridylaldimine+H⁺), 92 (38%, C₅H₄N—CH₂ ⁺), 119 (25%, C₅H₄N—CH═N—CH₂⁺), 294 (23%, M+2), 204 (22%, [M-(2-pyridylidene)]⁺), 79 (21%,pyridine⁺), 187 (20%, M-[2-pyridylineamino]⁺), 585 (1%, 2M+1).

[0406] b. Preparation of bis-(2-pyridylidene)-carbohydrazide(Carbo-Py-Al) With Formula:

[0407] The ligand was prepared using the method described by Exner O;Kliegman, J M; J. Org. Chem. 1971, 36, 2014-2015.

[0408] 8.96 g of anhydrous sodium sulphate (63.1 mmoles) and 4.0 ml of2-pyridylaldehyde (42.05 mmoles) were added in succession to asuspension of 1.89 g of carbohydrazide (21.0 mmoles) in 150 ml ofabsolute ethanol.

[0409] The reaction mixture was heated for 4 hours under reflux thenfiltered through a frit (the disappearance of the 2-pyridylaldehyde wasmonitored by gas chromatography).

[0410] The retained solid was washed with copious amounts of absoluteethanol to dissolve the product obtained.

[0411] The filtrate was concentrated to isolate a colourless solid,which was oven dried at 100° C. then re-crystallised from methanol.

[0412] 4.53 g of colourless crystals were obtained, corresponding to ayield of 80.5%.

[0413] The characteristics were as follows:

[0414] M.Pt: 219-220° C.;

[0415]¹H NMR/DMSO-d₆: δ 11.08 (wide s, 2H, NH), 8.58 (m, 2H, H_(2,13)),8.25 (wide s, 2H, H₆,), 8.12 (m, 2H, H_(5,10)), 7.87 (m, 2H, H_(4,11)),7.38 (m, 2H, H_(3,12));

[0416]¹³C NMR/DMSO-d₆: δ 153.46 (C7), 151.64 (C1 and C19), 149.26 (C2and C13), 143.69 (C6 and C8), 136.52 (C4 and C11), 123.83 (C3 and C12),119.75 (C5 and C10);

[0417] FAB+ (NBA matrix): 269 (60%, M+1), 148 (51%, [C₅H₄NCH═N—NHCO]⁺),122 (44%, C₅H₄N—CH═N—NH₃ ⁺), 107 (41%, 2-pyridylaldimine+H⁺), 537 (4%,2M+1), 559 (1%, 2M+Na⁺).

[0418] c. Preparation of 2-pyridylaldehyde N-methylhydrazone (Py-Alzone)With Formula:

[0419] The ligand was prepared using the method described by Exner O;Kliegman, J M; J. Org. Chem. 1971, 36, 2014-2015.

[0420] 8.96 g of anhydrous sodium sulphate (63.07 mmoles) and 2.24 ml ofN-methylhydrazine (42.05 mmoles) were added in succession to a solutionof 2.0 g of 2-pyridylaldehyde (21.02 mmoles) in 50 ml of absoluteethanol.

[0421] The reaction mixture was heated for 30 minutes at ambienttemperature, then heated for 20 hours under refulx, then filteredthrough a frit.

[0422] The isolated sodium sulphate was washed with diethyl ether.

[0423] The total filtrate was concentrated completely under reducedpressure.

[0424] The orange oil obtained underwent the usual treatment (extractionwith diethyl ether/water).

[0425] After drying over magnesium sulphate, filtering and concentrationunder reduced pressure, the yellow oil obtained was re-crystallised frommethanol.

[0426] The crystals obtained were washed with copious quantities ofpetroleum ether to render them colourless.

[0427] 1.4 g of crystals were obtained, corresponding to a yield of 49%.

[0428] The compound was relatively unstable and had to be prepared justprior to use.

[0429] The characteristics were as follows:

[0430] M.Pt: 44-45° C. (Lit: 39-40° C., obtained by Renwick, G M; Aust.J. Chem. 1970, 23, 2109-2117);

[0431]¹H NMR/CDCl₃: δ 8.50 (m, 1H, H₅), 7.71-7.76 (m, 1H, H₂), 7.57-7.66(m, 1H, H₃), 7.55 (s, 1H, H₆), 7.07-7.14 (m, 1H, H4), 5.92 (wide s, 1H,NH), 3.00 (s, 3H, H₇);

[0432]¹³C NMR/CDCl₃: δ 155.44 (Cl), 149.09 (C5), 136.21 (C3), 134.10(C6), 121.92 (C4), 119.04 (C2), 34.07 (C7);

[0433] GC/MS: Rt=13.75 min, M/Z=135, purity=100%.

[0434] d Preparation of 2-pyridylaldehyde semicarbazone(N-amido-PY-Alzone) With Formula:

[0435] 7.35 ml of triethylamine (52 mmoles) was added to a suspension of5.8 g of semicarbazide hydrochloride (52 mmoles) in 60 ml of absoluteethanol.

[0436] The solution was heated to 50° C. then 5 ml of 2-pyridylaldehydewas rapidly added.

[0437] The mixture was heated under reflux for two hours, cooled to 20°C. then filtered through a frit.

[0438] The isolated yellow solid was washed with copious amounts ofwater, oven dried at 100° C. then re-crystallised from ethanol.

[0439] 2.6 g of colourless crystals were otbained, which corresponded toa yield of 30%.

[0440] M.Pt: 204-206° C. (Lit: 206° C., EtOH obtained by Case, F H;Schilt, A A, J. Chem. Eng. Data 1980, 25, 404-405);

[0441]¹H NMR/DMSO-d₆: δ 10.56 (wide s, 1H, NH), 8.51 (m, 1H, H₅), 8.13(m, 1H, H₂), 7.90 (s, 1H, H₆), 7.77 (m, 1H, H₃), 7.30 (m, 1H, H4), 6.68(wide s, 2H, NH₂);

[0442]¹³C NMR/DMSO-d₆: δ 156.57 (C7), 153.66 (C1), 149.03 (C5), 139.85(C3), 136.32 (C6), 123.39 (C4), 119.50 (C2).

[0443] e—Preparation of trans-1,2-bis(2′-thienylideneamino)-cyclohexane(Chxn-Tho-Al) With Formula:

[0444] This ligand has been described by Van Stein, G C; Van Loten, G;Vrieze, K, Inorg. Chem 1985, 24 (9), 1367-1375.

[0445] 19.36 g of anhydrous magnesium sulphate (161.1 mmoles) and 6.44ml of rac-trans-1,2-diaminocyclohexane (53.6 mmoles) were successivelyadded to a solution of 10 ml of 2-thienylaldehyde (107.1 mmoles) in 75ml of absolute ethanol.

[0446] The reaction mixture was stirred for 16 hours at ambienttemperature (the solution thickened very rapidly), heated for 2 hoursunder reflux then filtered through a frit.

[0447] The isolated solid was washed with dichloromethane.

[0448] The total filtrate was concentrated completely under reducedpressure to isolate a brown solid which was re-crystallised fromethanol.

[0449] 14.0 g of beige crystals were obtained, corresponding to a yieldof 86%.

[0450] The characteristics were as follows:

[0451] M.Pt: 173-175° C. (EtOH);

[0452]¹H NMR/CDCl₃: δ 8.27 (s, 2H, H_(7,14)), 7.27 (m, 2H, H, ₂), 7.14(m, 2H, H_(5,16)), 6.96 (m, 2H, H_(3,4)), 3.32 (m, 2H, H_(8,13)), 1.82(m, 6H, H_(10,11) and H carried by carbons 9 and 12 located in theposition cis (or trans) with respect to the adjacent nitrogen atoms),1.44 (m, 2H, H carried by carbons 9 and 12 located in the trans (or cis)position with respect to the adjacent nitrogen atoms).

[0453]¹³C NMR/CDCl₃: δ 154.32 (C7 and C14), 142.54 (C6 to C15), 130.09(C1 and C2), 128.20 (C5 and C16), 127.18 (C3 and C4), 73.38 (C8 andC13), 32.83 (C9 and C12), 24.44 (C10 and C11).

[0454] f—Preparation of Glyoxal Dicyclohexylimine (DAB-Cy) With Formula:

[0455] A mixture composed of 6.53 g of an aqueous solution of 40% byweight glyoxal (45.0 mmoles of glyoxal), 7 ml of n-propanol and 20 ml ofwater was added to a solution of 10 g of cyclohexylamine (100.8 mmoles)in 70 ml of n-propanol.

[0456] After heating for one and a half hours at 70° C., the mixture wascooled to ambient temperature.

[0457] Adding 100 ml of ice water caused precipitation of a large amountof white solid.

[0458] It was isolated by filtering through a frit, washed with water(3×50 ml) and methanol (1×25 ml) then vacuum dried.

[0459] 8.5 g of product was obtained, corresponding to a yield of 86%.

[0460] The characteristics were as follows:

[0461] M.Pt: 144-145° C. (Literature: 145-147° C., obtained by Exner O;Kliegman, J M; J. Org. Chem. 1971, 36, 2014-2015);

[0462]¹H NMR/CDCl₃: δ 7.92 (s, 2H, H_(7,8)), 3.14 (m, 2H, H_(6,9)),1.17-1.82 (m, 20H, H_(1,2,3,4,5,10,11,12,13,14));

[0463]¹³C NMR/CDCl₃: δ 160.10 (C7 and C8), 69.39 (C6 to C9), 33.95 (C4,C5, C10 and C11), 25.50 (C1 and C14), 24.57 (C2, C3, C12 and C13).

[0464] Preparation of Catalysts:

[0465] The catalysts used were commercially available products with theexception of activated Cu (A) and activated Cu (B). An operating mode isalso provided for preparing said catalysts, which were then used in theexamples.

[0466] a—Activated Cu (A) Prepared by Purification of Metallic Copper:

[0467] A few grams of copper powder were ground for 15 minutes in asolution composed of 2 g of iodine dissolved in 100 ml of acetone.

[0468] The mixture was filtered through a frit, washed with 150 ml of asolution composed of concentrated hydrochloric acid (75 ml) and acetone(75 ml), using 100 ml of acetonitrile then 100 ml of acetone.

[0469] Elimination of all of the cuprous iodide was ensured by washingwith acetonitrile, a solvent in which it is highly soluble (27.51 g/l).

[0470] The activated copper was dried in a vacuum dessiccator in thepresence of P₂O₅.

[0471] It was used immediately after its preparation.

[0472] b—Activated Cu (B) Prepared by Reduction of Copper Sulohate:

[0473] 30 g of copper sulphate pentahydrate (120 mmoles) was dissolvedin a solution composed of 100 ml of distilled water and 5 ml ofhydrochloric acid.

[0474] 1.96 g of zinc (30 mmoles) was slowly added to this solution,taking care that the temperature did not exceed 40° C.

[0475] The precipitated copper was isolated by filtering through a frit,washed with distilled water then with acetone and dried in a desiccatorin the presence of P₂O₅.

[0476] It was used after preparation.

Example 1 N-arylation and N-vinylation of Azoles

[0477] Several operating protocols will now be given; their choicedepends on the physical form of the nucleophile and the arylation agent.

[0478] Operating Protocol A: Solid Nucleophile and Liquid ArylationAgent

[0479] 14.4 mg of cuprous oxide (0.1 mmoles), 116.8 mg of Chxn-Py-Al oranother ligand as generally defined in this patent (0.4 mmoles), 3mmoles of a nucleophilic compound and 1.303 g of caesium carbonate (4mmoles) are successively introduced into a 35 ml Schlenk tube that hasbeen oven dried at 100° C. and is provided with a magnetic stirrer(12×4.5 mm) and under a nitrogen atmosphere.

[0480] The Schlenk tube is purged under vacuum then refilled withnitrogen.

[0481] 2 mmoles of arylation agent then 1.2 ml of acetonitrile or DMFare then added using syringes.

[0482] The reactor is placed in an oil bath at a temperature of 82° C.and stirred for a period of one to five days.

[0483] Operating Protocol B: Solid Nucleophile and Solid Arylation Agent

[0484] 14.4 mg of cuprous oxide (0.11 mmoles), 116.8 mg of Chxn-Py-Al oranother ligand as generally defined in this patent (0.4 mmoles), 3mmoles of a nucleophilic compound, 2 mmoles of arylation agent and 1.303g of caesium carbonate (4 mmoles) are successively introduced into a 35ml Schlenk tube that has been oven dried at 100° C. and is provided witha magnetic stirrer (12×4.5 mm) and under a nitrogen atmosphere.

[0485] The Schlenk tube is purged under vacuum then refilled withnitrogen.

[0486] 1.2 ml of acetonitrile or DMF is then added using a syringe.

[0487] The reactor is placed in an oil bath at a temperature of 82° C.and stirred for a period of one to five days.

[0488] Operating Protocol C: Liquid Nucleophile and Arylation Agent

[0489] 14.4 mg of cuprous oxide (0.1 mmoles), 116.8 mg of Chxn-Py-Al oranother ligand as generally defined in this patent (0.4 mmoles) and1.303 g of caesium carbonate (4 mmoles) are successively introduced intoa 35 ml Schlenk tube that has been oven dried at 100° C. and is providedwith a magnetic stirrer (12×4.5 mm) and under a nitrogen atmosphere.

[0490] The Schlenk tube is purged under vacuum then refilled withnitrogen.

[0491] 3 mmoles of a nucleophilic compound, 2 mmoles of arylation agentand 1.2 ml of acetonitrile or DMF are then added using syringes.

[0492] The reactor is placed in an oil bath at a temperature of 82° C.and stirred for a period of one to five days.

[0493] Operating Protocol D: Liquid Nucleophile and Solid ArylationAgent

[0494] 14.4 mg of cuprous oxide (0.1 mmoles), 116.8 mg of Chxn-Py-Al oranother ligand as generally defined in this patent (0.4 mmoles), 2mmoles of a arylation agent and 1.303 g of caesium carbonate (4 mmoles)are successively introduced into a 35 ml Schlenk tube that has been ovendried at 100° C. and is provided with a magnetic stirrer (12×4.5 mm) andunder a nitrogen atmosphere.

[0495] The Schlenk tube is purged under vacuum then refilled withnitrogen.

[0496] 3 mmoles of nucleophilic compound and 1.2 ml of acetonitrile orDMF are then added using syringes.

[0497] The reactor is placed in an oil bath at a temperature of 82° C.and stirred for a period of one to five days.

[0498] Whichever operating protocol, A, B, C or D is used, the rest ofthe treatment is rigorously identical.

[0499] Determination of Isolated Yield:

[0500] After the period, the reaction mixture is diluted with 25 ml ofdichloromethane, filtered through celite, concentrated completely underreduced pressure (about 20 mm of mercury) then taken up in 50 ml ofdichloromethane.

[0501] This organic phase is extracted with distilled water (2×20 ml).

[0502] The aqueous phase is extracted again with 20 ml ofdichloromethane.

[0503] The total organic phase is washed with a saturated aqueous sodiumchloride solution (2×20 ml), dried over MgSO₄, filtered and concentratedunder reduced pressure.

[0504] The residue obtained is purified by silica gel chromatography(35-70 μm).

[0505] Determination of Degree of Transformation:

[0506] After the period, 65 μl of 1,3-dimethoxybenzene (internalreference) is introduced into the cooled reaction medium, which is thendiluted with 5 ml of diethyl ether or dichloromethane, depending on thesolubility of the products to be analysed.

[0507] An aliquot is then removed, filtered through celite (or filtermedium composed of about 90% SiO₂), eluting with diethyl ether ordichloromethane, extracted three times with distilled water thenanalysed by gas chromatography.

Example 1.1

[0508] Preparation of 1-phenyl-1H-pyrazole

[0509] Operating protocol A (82° C., 24 hours) was followed using 120.8mg of Chxn-Thio-Al (0.4 mmoles), 211 μl of bromobenzene (2 mmoles), 204mg of pyrazole (3 mmoles) and 1.2 ml of acetonitrile.

[0510] The residue obtained was purified by silica gel chromatography(eluent: dichloromethane/petroleum ether 60/40).

[0511] A colourless liquid was obtained in a yield of 80% by weight.

[0512] The compound obtained had the following formula:

[0513] The characteristics were as follows:

[0514] B.Pt: 58° C., 0.2 mm Hg (Lit: 58-60° C., 0.2 mm Hg);

[0515]¹H NMR/CDCl₃ (250 MHz): δ 7.92 (dd, 1H, ³J_(HH)=2.4 Hz,4J_(HH)=0.5 Hz, H₅), 7.70 (m, 3H, H_(3,6,9)), 7.45 (m, 2H, H_(2,8)),7.29 (s, 1H, H₁), 6.46 (dd, 1H, ³J_(HH)=2.4 Hz, 3J_(HH)=1.8 Hz, H₄);

[0516]¹³C NMR/CDCl₃: δ 141.08 (C3), 140.23 (C7), 129.43 (C2 and C8),126.75 (C5), 126.44 (C1), 119.21 (C6 and C9), 107.61 (C4);

[0517] GC/MS: Rt=15.37 min, M/Z=144, purity=100%;

[0518] Rf=0.40 (eluent: dichloromethane/petroleum ether, 60/40).

Example 1.2

[0519] Preparation of 1-phenyl-1H-pyrazole

[0520] Operating protocol A (82° C., 24 hours) was followed using 117 mgof Chxn-Py-Al (0.4 mmoles), 211 μl of bromobenzene (2 mmoles), 204 mg ofpyrazole (3 mmoles) and 1.2 ml of acetonitrile.

[0521] The residue obtained was purified by silica gel chromatography(eluent: dichloromethane/petroleum ether 60/40).

[0522] A yield of 93:1% by weight of 1-phenyl-1H-pyrazole was obtainedwith formula:

Example 1.3

[0523] Preparation of 1-phenyl-1H-pyrazole

[0524] Operating protocol A (82° C., 24 hours) was followed using 54 mgof Py-Alzone (0.4 mmoles), 211 μl of bromobenzene (2 mmoles), 204 mg ofpyrazole (3 mmoles) and 1.2 ml of acetonitrile.

[0525] The residue obtained was purified by silica gel chromatography(eluent: dichloromethane/petroleum ether, 60/40).

[0526] A yield of 96.7% by weight of 1-phenyl-1H-pyrazole was obtainedwith formula:

Example 1.4

[0527] Preparation of 1-phenyl-1H-pyrazole

[0528] Operating protocol A (82° C., 24 hours) was followed using 65.6mg of N-Amido-Py-Alzone (0.4 mmoles), 211 μl of bromobenzene (2 mmoles),204 mg of pyrazole (3 mmoles) and 1.2 ml of acetonitrile.

[0529] The residue obtained was purified by silica gel chromatography(eluent: dichloromethane/petroleum ether 60/40).

[0530] A yield of 95.2% by weight of 1-phenyl-1H-pyrazole was obtainedwith formula:

Example 1.5

[0531] Preparation of 1-phenyl-1H-pyrazole

[0532] Operating protocol A (82° C., 24 hours) was followed using 107.2mg of Carbo-Py-Al (0.4 mmoles), 211 μl of bromobenzene (2 mmoles), 204mg of pyrazole (3 mmoles) and 1.2 ml of acetonitrile.

[0533] The residue obtained was purified by silica gel chromatography(eluent: dichloromethane/petroleum ether 60/40).

[0534] A yield of 75% by weight of 1-phenyl-1H-pyrazole was obtainedwith formula:

Example 1.6

[0535] Preparation of 1-(o-tolyl)-1H-pyrazole

[0536] Operating protocol A (82° C., 70 hours) was followed using 117 mgof Chxn-Py-Al (0.4 mmoles), 383 μl of 2-iodotoluene (3 mmoles), 136 mgof pyrazole (2 mmoles) and 1.2 ml of acetonitrile.

[0537] The degree of transformation and selectivity for1-(o-tolyl)-1H-pyrazole were 100%.

[0538] The residue obtained was purified by silica gel chromatography(eluent: hexane/dichloromethane, 100/0 to 0/100).

[0539] 297 mg of a pale yellow oil was obtained, corresponding to ayield of 94% by weight.

[0540] The compound obtained had the following formula:

Example 1.7

[0541] Preparation of 1-(4′-bromophenyl)-1H-pyrazole

[0542] Operating protocol B (82° C., 72 hours) was followed using 117 mgof Chxn-Py-Al (0.4 mmoles), 1.887 g of 1,4-dibromobenzene (8 mmoles),136 mg of pyrazole (3 mmoles) and 1.6 ml of acetonitrile.

[0543] The degree of transformation and selectivity for1-(4′-bromophenyl)-1H-pyrazole were 89%.

[0544] The residue obtained was purified by silica gel chromatography(eluent: hexane/dichloromethane, 100/0 to 50/50).

[0545] 366 mg of a colourless solid was obtained, corresponding to ayield of 82% by weight.

[0546] The compound obtained had the following formula:

[0547] The characteristics were as follows:

[0548] M Pt: 71° C. (MeOH) (Lit: 70° C., aqueous MeOH obtained by Khan,M A; Lynch, B M; Hung, Y-Y; Can. J. Chem. 1963, 41,1540-1547);

[0549]¹H NMR/CDCl₃ (250 MHz): δ 7.88 (dd, 1H, ³J_(HH)=2.5 Hz, ⁴J_(HH)=OS Hz, H ₅), 7.72 (dd, 1H, ³J_(HH)=1.7 Hz, ⁴J_(HH)=0.5 Hz, H₃),7.52-7.62 (m, 4H, H_(6,7,8,9)), 6.46 (dd, 1H, ′J_(HH)=1.7 Hz,³J_(HH)=2.5 Hz, H₄);

[0550]¹³C NMR/CDCl₃: δ 141.41 (C3), 139.21 (C1), 132.46 (C6 and C7),126.64 (C5), 120.59 (C8 and C9), 119.62 (C2), 108.83 (C4);

[0551] GC/MS: Rt=16.90 min, M/Z=222 and 224, purity=100%;

[0552] Rf=0.21 (eluent: hexane/dichloromethane, 50/50).

Example 1.8

[0553] Preparation of 1-(4-imidazol-1-yl-phenyl)-1H-pyrazole

[0554] Operating protocol B (82° C., 48 hours) was followed using 117 mgof Chxn-Py-Al (0.4 mmoles), 535 mg of 1-(4′-bromophenyl)-1H-imidazole(2.4 mmoles), 136 mg of pyrazole (2 mmoles) and 1.2 ml of acetonitrile.

[0555] The residue obtained was purified by silica gel chromatography(eluent: dichloromethane/methanol, 100/0 to 98/2).

[0556] 387 mg of a colourless solid was obtained, corresponding to ayield of 92% by weight.

[0557] The compound obtained had the following formula:

[0558] The characteristics were as follows:

[0559] M Pt: 174-176° C.;

[0560]¹H NMR/acetone-d₆ (250 MHz): δ 8.40 (dd, 1H, ³J_(HH)=2.5 Hz,⁴J_(HH)=0.6 Hz, Hs) 8.15 (wide s, 1H, H₁₁), 7.98-8.04 (m, 2H, H_(7,8)),7.73-7.79 (m, 2H, H_(2,6)), 7.73 (dd, 1H, J_(HH)=1.7 Hz, ⁴J_(HH)=0.6 Hz,H₃), 7.66 (wide s, 1H, H₁₀), 7.16 (wide s, 1H, H₁₂), 6.54 (dd, 1H,³J_(HH)=1.7 Hz, ³J_(HH)=2.5 Hz, H₄);

[0561]¹³C NMR/DMSO-d₆: δ 141.28 (C3), 138.57 (C1), 135.27 (C11), 134.12(C9), 127.92 (C5), 127.54 (C12), 121.75 (C2 and C6), 119.36 (C7 and C8),118.68 (C10), 108.12 (C4);

[0562] GC/MS: Rt=22.49 min, M/Z=210, purity=100%;

[0563] Rf=0.22 (eluent: diethyl ether/methanol, 90/10).

Example 1.9

[0564] Preparation of 1H, ′H-1,1′-p-phenylene-bis-pyrazole

Example 1.8 was repeated, replacing the 1-(4′-bromophenyl)-1H-imidazolewith 1-(4′-bromophenyl)-1H-pyrazole (2.4 mmoles, 535 mg).

[0565] Pale yellow crystals were obtained which could be renderedcolourless by re-crystallisation from chloroform.

[0566] The degree of transformation and isolated yield were 100%.

[0567] The compound obtained had the following formula:

[0568] The characteristics were as follows:

[0569] M Pt: 180° C. (CHCl₃): (Lit: 182° C., CHCl₃ obtained byKauffmann, T; Lexy, H., Chem. Ber. 1980, 113, 2749-2754);

[0570]¹H NMR/CDCl₃ (250 MHz): δ 7.95 (dd, 1H, ³J_(HH)=2.5 HZ,⁴J_(HH)=0.6 Hz, H₅), 7.79 (s, 2H, H_(2,6)), 7.74 (dd, 1H, ³J_(HH)=1.6Hz, ⁴J_(HH)=0.6 Hz, H₃), 6.49 (dd, 1H, ³J_(HH)=1.6 Hz,3J_(HH)=2.5 Hz,H₄);

[0571]¹³C NMR/CDCl₃: δ 141.31 (C3), 138.41 (C1), 126.74 (C5), 120.04 (C2and C6), 107.90 (C4);

[0572] GC/MS: Rt=21.28 min, M/Z=210, purity=98%;

[0573] Rf=0.38 (eluent: dichloromethane/ethyl acetate, 90/10).

Example 1.10

[0574] Preparation of 1-trans-styryl-1H-pyrazole

[0575] Operating protocol A (82° C., 24 hours) was followed using 117 mgof Chxn-Py-Al (0.4 mmoles), 387 μl, of β-bromostyrene (3 mmolestrans/cis=91/9), 136 mg of pyrazole (2 mmoles) and 1.2 ml ofacetonitrile.

[0576] The residue obtained was purified by silica gel chromatography(eluent: hexane/dichloromethane 100/0 to 50/50).

[0577] 327 mg of a pale yellow solid was obtained, corresponding to ayield of 96% by weight.

[0578] The compound obtained had the following formula:

[0579] The characteristics were as follows:

[0580] M Pt: 53° C.;

[0581]¹H NMR/CDCl₃ (250 MHz): δ 7.66-7.67 (m, 2H, H_(3,5)), 7.52 (d, 1H,³J_(HH)=14.5 Hz, H₁), 7.22-7.48 (m, 5H, H₇it), 7.06 (d, 1H, ³J_(HH)=14.5Hz, H₂), 6.40 (m, 1H, H₄). The value of the coupling constant ³J_(H1H2)proves that the phenyl and pyrazolyl substituents of the ethylenic bondare located in the trans position. The coupling constants ⁴J_(H3H5),³J_(H3H4) and ³J_(H4H5) could not be calculated as the signals wereperturbed by coupling with the H₁ proton.

[0582]¹³C NMR/CDCl₃: δ 141.13 (C3), 135.09 (C6), 128.89 (C8 and C10),128.14 (C1), 127.60 (C9), 126.48 (C5), 126.26 (C7 and C11), 116.88 (C2),107.34 (C4);

[0583] GC/MS: Rt=17.05 min, M/Z=170, purity=98%;

[0584] Rf=0.22 (eluent: hexane/dichloromethane, 50/50).

Example 1.11

[0585] Preparation of 3,5-dimethyl-1-phenyl-1H-pyrazole

[0586] Operating protocol A (110° C., 54 hours) was followed using 117mg of Chxn-Py-Al (0.4 mmoles), 336 μl of iodobenzene (3 mmoles), 192 mgof 3,5-dimethylpyrazole (2 mmoles) and 1.2 ml of DMF. The degree oftransformation and selectivity for 5-dimethyl-1-phenyl-1H-pyrazole were100%.

[0587] The residue obtained following the treatment was purified bysilica gel chromatography (eluent: hexane/dichloromethane, 100/0 to10/90).

[0588] 323 mg of a yellow oil was obtained, corresponding to a yield of94% by weight.

[0589] The compound obtained had the following formula:

[0590] The characteristics were as follows:

[0591]¹H NMR/CDCl₃ (250 MHz): δ 7.25-7.40 (m, 5H, H_(7,8,9,10,11)), 5.95(broad s, 1H, H₄), 2.27 (d, ⁴J_(HH)=0.8 Hz, 3H, H₂), 2.25 (broad s, 3H,HI). Only the coupling constant between the protons of the methyl grouplocated in the 5 position and H₄ could be determined. The couplingconstant between the protons of the methyl group lcoated in the 3position and H₄ was too small to be read;

[0592]¹³C NMR/CDCl₃: δ 148.86 (C3), 140.00 (C6), 139.28 (C5), 128.93 (C8and C10), 127.14 (C9), 124.69 (C7 and C11), 106.92 (C4), 13.48 (C2),12.31 (C1) [De la Hoz, A; Pardo, M C; Elguero, J; Fruchier, A; Magn.Reson. Chem. 1989, 27, 603-606].

[0593] GC/MS: Rt=15.30 min, M/Z=172, purity=99%;

[0594] Rf=0.17 (eluent: dichloromethane).

Example 1.12

[0595] Preparation of 3,5-dimethyl-1-phenyl-1H-pyrazole

[0596] Operating protocol A (110° C., 24 hours) was followed using 117mg of Chxn-Py-Al (0.4 mmoles), 336 μl of iodobenzene (3 mmoles), 192 mgof 3,5-dimethylpyrazole (2 mmoles) and 1.2 ml of DMF.

[0597] The degree of transformation and selectivity for5-dimethyl-1-phenyl-1H-pyrazole were 75%.

[0598] The compound obtained had the following formula:

Example 1.13

[0599] Preparation of 1-phenyl-1H-pyrazole

[0600] Operating protocol A (82° C., 48 hours) was followed using 117 mgof Chxn-Py-Al (0.4 mmoles), 211 μl of bromobenzene (2 mmoles), 204 mg ofimidazole (3 mmoles) and 1.2 ml of acetonitrile.

[0601] The yellow oil obtained following treatment was purified bysilica gel chromatography (eluent: dichloromethane/ethyl acetate, 100/0to 50/50).

[0602] A pale yellow oil corresponding to l-phenyl-1H-imidazole wasobtained in a yield of 80% and had formula:

[0603] The characteristics were as follows:

[0604] H NMR/CDCl₃: 6 (Collman, J P; Zhong, M; Org. Lett. 2000, 2,1233-1236, Supporting Information) 7.84 (dd, 1H, ⁴J_(HH)=1.3 Hz,⁴J_(HH)=1.0 Hz, H₁), 7.43-7.53 (m, 2H, H_(6,8)), 7.32-7.41 (m, 3H,H_(5,7,9)), 7.28 (t, 1H, ³J_(HH)=1.3 Hz, ⁴J_(HH)=1.3 Hz, H₃), 7.19 (dd,1H, ³J_(HH)=1.3 Hz, ⁴J_(HH)=1.0 Hz, H₂);

[0605]¹³C NMR/acetone-d₆: δ 138.46 (C4), 136.37 (C1), 131.16 (C2),130.77 (C6 and C8), 127.88 (C7), 121.69 (C5 and C9), 118.77 (C3);

[0606] GC/MS: Rt=14.76 min, M/Z=144, purity=100%;

[0607] Rf=0.17 (eluent: dichloromethane/ethyl acetate, 50/50).

Example 1.14

[0608] Preparation of 1-(4′-trifluoromethylphenyl-1H-imidazole

[0609] General procedure A (82° C., 48 hours) was followed using 72 mgof cuprous oxide (0.5 mmoles), 585 mg of Chxn-Py-Al (2 mmoles), 1.40 mlof 4-bromotrifluormethylbenzene (10 mmoles), 1.02 g of imidazole (15mmoles), 5.86 g of caesium carbonate (18 mmoles) and 6 ml ofacetonitrile.

[0610] The residue obtained was purified by silica gel chromatography(eluent: hexane/dichloromethane, 100/0 to 0/100).

[0611] 359 mg of a pale yellow solid was obtained in a yield of 85%.

[0612] The compound obtained had the following formula:

[0613] The characteristics were as follows:

[0614] MPt: 70° C.;

[0615]¹H NMR/CDCl₃:δ 7.90 (wide s, 1H, H₁), 7.72 (m, 2H, H_(5,9)), 7.49(m, 2H, H_(6,8)), 7.31 (wide s, 1H, H₃), 7.22 (s, 1H, H₂);

[0616]¹³C NMR₁ DMSO-d₆: δ 8.43 (wide s, 1H, Hi), 7.85-7.95 (m, 5H,H_(3,5,6,8,9)), 7.22 (s, 11H, H₂);

[0617]¹³C NMR/CDCl₃: 139.99 (C4), 135.52 (C1), 131.20 (C2),129.47 (q,J_(CF)=33.2 Hz, C7), 127.23 (q, ³J_(CF)=3.8 Hz, C6 and C8), 123.63 (q,¹J_(CF)=272.1 Hz, C10), 121.25 (C5 and C9), 118.26 (C3);

[0618]¹⁹F NMR/CDCl₃: δ−62.92 (CF₃);

[0619] GC/MS: Rt=14.82 min, M/Z=212, purity=98%;

[0620] Rf=0.20 (eluent: dichloromethane).

Example 1.15

[0621] Preparation of 1-phenyl-1H-indole

[0622] Operating protocol A (82° C., 24 hours) was followed using 117 mgof Chxn-Py-Al (0.4 mmoles), 224 μl of iodobenzene (2 mmoles), 351 mg ofindole (3 mmoles) and 1.2 ml of acetonitrile.

[0623] The degree of transformation and selectivity for1-phenyl-1H-indole were 99.5%.

[0624] The red oil obtained following treatment was purified by silicagel chromatography (eluent: hexane/dichloromethane, 100/0 to 50150).

[0625] A yellow-green oil was obtained in a yield of 92%.

[0626] The compound obtained had the following formula:

[0627] The characteristics were as follows:

[0628]¹H NMR/CDCl₃:δ 7.74-7.80 (m, 1H, H₅), 7.62-7.68 (m, 1H, Hg),7.51-7.58 (m, 4H, H_(10,11,12,13)), 7.34-7.47 (m, 1H, H₁₄), 7.40 (d,³J_(HH)=3.3 Hz,1H, H₂); 7.20-7.33 (m, 2H, H_(6,7)), 6.76 (dd, 1H,³J_(H3H2)=3.3 Hz, ³J_(H3H8)=0.9 Hz, H₃). The attributions were made bymeans of a COSY H—H experiment.

[0629]¹³C NMR/CDCl₃: 139.90 (C1), 135.93 (C9), 129.67 (C10 and C11),129.41 (C4), 128.02 (C14), 126.50 (C2), 124.44 (C12 and C13), 122.43(C6), 121.21 (C5), 120.43 (C7), 110.58 (C8), 103.65 (C3).

[0630] GC/MS: M/Z=193, purity=100%;

[0631] Rf=0.23 (eluent: hexane).

Example 1.16

[0632] Preparation of 1-phenyl-1H-indole

[0633] Operating protocol A (50° C., 74 hours) was followed using 117 mgof Chxn-Py-Al (0.4 mmoles), 224 μl of iodobenzene (2 mmoles), 351 mg ofindole (3 mmoles) and 1.2 ml of acetonitrile.

[0634] The degree of transformation and selectivity for1-phenyl-1H-indole was 99%.

[0635] The compound obtained had the following formula:

Example 1.17

[0636] Preparation of 1-phenyl-1H-1,2,41 triazole

[0637] Operating protocol A (82° C., 48 hours) was followed using 117 mgof Chxn-Py-Al (0.4 mmoles), 336 μl of iodobenzene (3 mmoles), 138 mg of1,2,4-triazole (2 mmoles), 1.042 g of caesium carbonate (3.2 mmoles) and1.2 ml of DMF.

[0638] The degree of transformation and selectivity were 100% and 98%respectively.

[0639] The residue obtained following treatment was purified by silicagel chromatography (eluent: hexane/dichloromethane, 100/0 to 50/50).

[0640] 264 mg of a dark yellow solid was obtained in a yield of 91%.

[0641] Pale yellow needles were obtained after re-crystallisation fromchloroform.

[0642] The compound obtained had the following formula:

[0643] The characteristics were as follows:

[0644] MPt: 46° C. (CHCl₃) (Lit: 46-47° C. given by Micetich, R G;Spevak, P; Hall, T W; Bains, B K; Heterocycles 1985, 23, 1645-1649);

[0645] H NMR/CDCl₃:δ 8.52 (wide s, 1H, HI), 8.04 (wide s, 1H, H₂),7.53-7.65 (m, 2H, H_(4,8)), 7.26-7.51 (m, 3H, H_(5,6,7));

[0646]¹³C NMR/CDCl₃: δ 152.55 (C1), 140.88 (C2), 139.96 (C3), 129.73 (C5and C7), 128.15 (C6), 119.99 (C4 and C8);

[0647] GC/MS: Rt=14.02 min, M/Z=145, purity=100%;

[0648] Rf=0.21 (eluent: dichloromethane/ethyl acetate, 90/10).

Example 1.18

[0649] Preparation of 1-phenyl-1H-[1,2,4]triazole

[0650] Operating protocol A (82° C., 24 hours) was followed using 117 mgof Chxn-Py-Al (0.4 mmoles), 336 μl of iodobenzene (3 mmoles), 138 mg of1,2,4-triazole (2 mmoles), 1.042 g of caesium carbonate (3.2 mmoles) and1.2 ml of DMF.

[0651] The degree of transformation and selectivity were 79% and 99%respectively.

Example 1.19

[0652] Preparation of 1-phenyl-1H-[1,2,4]triazole

Example 1.18 was repeated, operating at 50° C. (72 hours). The degree oftransformation and selectivity for 1-phenyl-1H-[1,2,4-triazole] were 75%and 99% respectively.

[0653]

Example 1.20

[0654] Preparation of 1-phenyl-1H-pyrrole

[0655] Operating protocol C (50° C., 4 days) was followed using 117 mgof Chxn-Py-Al (0.4 mmoles), 269 μl of iodobenzene (2.4 mmoles), 208 μlof pyrrole (2 mmoles) and 1.2 ml of acetonitrile.

[0656] The residue obtained was purified by silica gel chromatography(eluent: hexane).

[0657] The yield and degree of transformation of 1-phenyl-1H-pyrrolewere 100%.

[0658] The compound obtained had the following formula:

[0659] The characteristics were as follows:

[0660] MPt: 62° C. (Lit: 62° C. obtained by Dumoulin, H; Rauly, S;Robba, M; J. Heterocycl. Chem. 1995, 32, 1703-1707);

[0661]¹H NMR/CDCl₃:δ 7.50-7.60 (m, 4H, H_(5,7,1,10)), 7.38 (m, 1H, H₆),7.26 (m, 2H, H_(1,4)), 6.54 (m, 2H, H_(2,3));

[0662]¹³C NMR/CDCl₃: δ 140.96 (C9), 129.71 (C5 and C7), 125.74 (C6),120.64 (C8 and C10), 119.44 (C I and C4), 110.68 (C2 and C3);

[0663] GC/MS: Rt=12.75 min, M/Z=143, purity=99%;

[0664] Rf=0.33 (eluent: hexane).

Example 1.21

[0665] Preparation of 1-phenyl-1H-pyrrole

[0666] Operating protocol C (82° C., 4 days) was followed using 117 mgof Chxn-Py-Al (0.4 mmoles), 253 μl of bromobenzene (2.4 mmoles), 208 μlof pyrrole (2 mmoles) and 1.2 ml of acetonitrile.

[0667] The residue obtained was purified by silica gel chromatography(eluent: hexane).

[0668] The degree of transformation of 1-phenyl-1H-pyrrole was 70%.

[0669] The compound obtained had the following formula:

Example 1.22

[0670] Preparation of 1-(4′-aminophenyl)-1H-pyrazole

[0671] General procedure B (82° C., 42 hours) was followed using 117 mgof Chxn-Py-Al (0.4 mmoles), 516 mg of 4-bromoaniline (3 mmoles), 136 mgof pyrazole (2 mmoles) and 1.2 ml of acetonitrile.

[0672] The brown oil obtained after the filtration step was purifieddirectly by alumina chromatography (eluent: hexane/dichloromethane,100/0 to 50/50).

[0673] 290 mg of an orange solid was obtained, corresponding to a yieldof 91%.

[0674] The treatment and analyses were carried out as quickly aspossible protected from the light as there was a risk that the compoundwould decompose.

[0675] The compound obtained had the following formula:

[0676] The characteristics were as follows:

[0677] MPt: 42-43° C.;

[0678]¹H NMR/CDCl₃ (250 MHz):δ 7.75 (dd, 1H, ³J_(HH)=2.4 Hz, ⁴J_(HH)=0.5HZ, H₅), 7.66 (dd, 1H, ³J_(HH)=1.8 Hz, ??=0.5 Hz, H₃), 7.40 (m, 2H,H_(6,7)), 6.66 (m, 2H, H_(8,9)), 6.38 (dd, 1H, ³J_(HH)=?? Hz,³J_(HH)=2.4 Hz, H₄) 3.79 (s, 2H, NH₂). Purity=98%;

[0679]¹³C NMR/CDCl₃: δ 145.47 (C2), 140.22 (C3), 132.31 (Cl), 126.80(C5), 121.10 (C6, C7), 115.43 (C8, C9), 106.83 (C4);

[0680] GC/MS: Rt=17.77 min, M/Z=159;

[0681] Rf=0.17 (eluent: dichloromethane/ethyl acetate, 95/5, silica) or0.17 (eluent: dichloromethane/hexane, 50/50, alumina).

Example 1.23

[0682] Preparation of 1-methyl-4-(1H-pyrazol-l′-yl)-1H-pyrazole

[0683] The preceding example was repeated, using pyrazole and1-methyl-4-bromopyrazole.

[0684] The compound obtained had the following formula:

[0685] The characteristics were as follows:

[0686] M.Pt: 63-64° C.;

[0687]¹H NMR/acetone-d₆ (250 MHz): δ 8.00 (dd, 1H, ³J_(HH)=2.4 HZ,⁴J_(HH)=0.65 Hz, H₅), 8.00 (d, 1H, ⁴J_(HH)=0.75 Hz, H₇), 7.77 (d, 1H,⁴J_(HH)=0.75 Hz, H₂), 7.60 (dd, 1H, ³J_(HH)=1.85 Hz, ⁴J_(HH)=0.65 Hz,H₃), 6.41 (dd, H, ³J_(HH)=1.85 Hz, ³J_(HH)=24H₁H₄), 3.94 (s, 3H, H₁);

[0688]¹³C NMR/CDCl₃: δ 140.34 (C3), 130.55 (C5), 127.98 (C2), 126.30(C6), 121.93 (C7), 106.68 (C4), 39.51 (C1);

[0689] GC/MS: Rt=14.13 min, M/Z=148, purity=99%;

[0690] FAB+(NBA matrix): 149 (100%, M+H⁺), 55 (24%), 148 (22%), 69 (20%,pyrazole+H⁺), 297 (3%, 2M+1);

[0691] HRMS: Calculated for C₇H₉N₄(M⁺+H): 149.0827. Found: 149.0819;

[0692] Rf: 0.28 (eluent: dichloromethane/methanol, 98/2).

Example 1.24

[0693] Preparation of 1-phenyl-3-trifluoromethyl-5-(p-tolyl)-1H-pyrazole

[0694] This compound was isolated by silica gel chromatography followingarylation of 3-trifluoromethyl-5-(p-tolyl)-1H pyrazole using iodobenzeneas described in Example 1.1.

[0695] The compound obtained had the following formula:

[0696] The characteristics were as follows:

[0697]¹H NMR/acetone-d₆: δ 7.39-7.46 (m, 3H, H_(13,14,15)), 7.33-7.38(m, 2H, H_(11,12)), 7.19 (m, 4H, H₆₉), 6.94 (q, 1H¹⁴J_(HF)=0.6 Hz, H₄),2.32 (s, 3H, H₂);

[0698]³C NMR/acetone-d₆: δ 146.01 (C5), 143.32 (q, ²J_(CF)=38.0 Hz, C3),140.48 (C17), 139.95 (C16), 130.16 (C13 and C14), 129.99 (C8 and C9),129.65 (C6 and C7), 129.44 (C15), 127.20 (C10), 126.51 (C11 and C12),122.64 (q, ′J_(CF)=268.3 Hz, C1), 106.01 (q, ³J_(CF)=1.9 Hz, C4), 21.20(C2). Carbons 6-9 have similar chemical displacements, which agrees withthe fact that the signals for protons 6-9 are superimposed;

[0699]¹⁹F NMR/acetone-d₆: δ −63.05 (d, ⁴J_(HF)=0.6 Hz), purity=99.8%;

[0700] GC/MS: Rt=20.54 min, M/Z=302, purity>99.5%;

[0701] Rf: 0.30 (eluent: hexane/dichloromethane, 80/20).

Example 1.25

[0702] Preparation of1-phenyl-3-(i)-tolyl)-5-trifluoromethyl-1H-pyrazole

[0703] As described for the preceding example, this compound wasisolated by arylation of 3-trifluoromethyl-5-(p-tolyl)-1H pyrazole usingiodobenzene.

[0704] The compound obtained had the following formula:

[0705] The characteristics were as follows:

[0706]¹cNMR/acetone-d₆: δ 152.44 (C3), 140.12 (q, J_(CF)=18.2 Hz, C5),139.31 (C16), 134.48 (C17), 130.26 (C8, C9 and C15), 130.06 (C13 andC14), 127.21 (C10), 126.64 (q, ⁶J_(CF)=0.4 Hz, C6 and C7) 126.48 (C11and C12), 120.95 (q, ¹C=283H, C1) 106.01 (q 2.6 Hz, C4), 21.23 (C2).;

[0707]¹⁹FNMR acetone-d₆:δ −58.51(s);

[0708] GC/MS: Rt=21.16 min, m/z=302, purity=98%;

[0709] Rf: 0.34 (eluent: hexane/dichloromethane, 80/20).

Example 1.26

[0710] Preparation of5-(3-chlorosulphonl-4-methylphenyl)-1-phenyl-3-trifluoromethyl-1H-pyrazole

[0711] As described for in Example 1.24, this compound was obtained byarylation of 5-(3-chlorosulphonyl-4-methylphenyl)-3-trifluoromethyl-1Hpyrazole using iodobenzene.

[0712] The compound obtained had the following formula:

[0713] The characteristics were as follows:

[0714]¹H NMR/CDCl₃: δ 7.94 (m, 1H, H₇), 7.40-7.47 (m, 3H), 7.37-7.39 (m,2H), 7.27-7.35 (m, 2H), 6.87 (m, 1H, H4), 2.78 (s, 3H, H₂). Purity: 95%;

[0715] GC/MS: R_(t) 25.92 min, M/Z=400 and 402;

[0716] Rf: 0.24 (eluent: hexane/dichloromethane, 80/20).

Example 2 N-arylation of Amides, Carbamates and Derivatives GeneralOperating Protocol

[0717] The following are successively introduced into a 35 ml Schlenktube placed in a nitrogen atmosphere:

[0718] cuprous oxide (0.1 mmoles);

[0719] ligand (0.4 mmoles);

[0720] nucleophilic compound (3 mmoles);

[0721] a base (4 mmoles);

[0722] 2 mmoles of arylation agent;

[0723] and 1.2 ml of acetonitrile or DMF

[0724] The mixture is placed in an oil bath at a temperature of 82° C.and stirred for 24 hours. After this period, the mixture is diluted withethyl ether or dichloromethane.

[0725] Determination of Isolated Yield:

[0726] After the period, the reaction mixture is diluted with 25 ml ofdichloromethane, filtered through celite, concentrated completely underreduced pressure then taken up in 50 ml of dichloromethane.

[0727] This organic phase is extracted with distilled water (2×20 ml).

[0728] The aqueous phase is extracted again with 20 ml ofdichloromethane.

[0729] The total organic phase is washed with a saturated aqueous sodiumchloride solution (2×20 ml), dried over MgSO₄, filtered and concentratedunder reduced pressure.

[0730] The residue obtained is purified by silica gel chromatography(35-70 μm).

[0731] Determination of Degree of Transformation:

[0732] After the period, 65 μl of 1,3-dimethoxybenzene (internalreference) is introduced into the cooled reaction medium, which is thendiluted with 5 ml of diethyl ether or dichloromethane, depending on thesolubility of the products to be analysed.

[0733] An aliquot is then removed, filtered through celite, eluting withdiethyl ether or dichloromethane, extracted three times with distilledwater then analysed by gas chromatography.

Example 2.1

[0734] Preparation of 3-ohenyloxazolidin-2-one

[0735] 14.4 mg of cuprous oxide (0.1 mmoles), 117 mg of Chxn-Py-Al (0.4mmoles), 263 mg of oxazolidin-2-one (3 mmoles), 1.043 g of caesiumcarbonate (3.2 mmoles) and 600 mg of ground and activated 3 A molecularsieve (K_(n)Na_(12,-n)[(AlO₂)₁₂(SiO₂)₁₂]) were successively introducedinto a 35 ml Schlenk tube that had been oven dried at 1001C and providedwith a magnetic stirrer (12×4.5 mm) and under a nitrogen atmosphere.

[0736] The Schlenk tube was purged under vacuum then refilled withnitrogen.

[0737] 224 μl of iodobenzene (2 mmoles) then 1.2 ml of DMF were thenadded using syringes.

[0738] The reactor was placed in an oil bath at a temperature of 82° C.and stirred for a period of 24 hours.

[0739] The degree of transformation of 3-phenyloxazolidin-2-one was99.7% and the selectivity reached 100%.

[0740] After the period, the reaction mixture was diluted with 25 ml ofdichloromethane, filtered through celite, concentrated completely underreduced pressure then taken up in 50 ml of dichloromethane.

[0741] This organic phase was extracted with distilled water (2×20 ml).

[0742] The aqueous phase is extracted again with 20 ml ofdichloromethane.

[0743] The total organic phase was washed with a saturated aqueoussodium chloride solution (2×20 ml), dried over MgSO₄, filtered andconcentrated under reduced pressure.

[0744] The residue obtained was purified by silica gel chromatography(eluent: hexane/dichloromethane, 50/50 to 0/100).

[0745] 316 mg of a colourless solid was obtained, corresponding to ayield of 97%.

[0746] The compound obtained had the following formula:

[0747] The characteristics were as follows:

[0748] M.Pt: 120° C. (Lit: 120-121° C., given by Gulbins, E; Hamann, K;Chem. Ber. 1966, 99, 55-61);

[0749]¹H NMR/CDCl₃: δ 7.48-7.53 (m, 2H, H_(3,5)), 7.30-7.38 (m, 2H,H_(2,6)), 7.07-7.15 (m, 1H, H₄), 4.40 (m, 2H, H₈, ³J_(HH)=8.00 Hz), 3.97(m, 2H, Hg, ³J_(HH)=8.0 Hz);

[0750]¹³ C NMR/CDCl₃: δ 155.34 (C7), 138.30 (C1), 129.04 (C3 and C5),124.01 (C4), 118.22 (C2 and C6), 61.37 (C8), 45.14 (C9);

[0751] GC/MS: Rt=18.25 min, M/Z=163, purity=1100%;

[0752] Rf: 0.29 (eluent: dichloromethane).

Example 2.2

[0753] Preparation of 3-phenyloxazolidin-2-one

Example 2.1 was repeated, heating for 96 h at 50° C.

[0754] The degree of transformation of 3-phenyloxazolidin-2-one was99.6% and the selectivity reached 100%.

Example 2.3

[0755] Preparation of 1-phenyl-1H-pyridin-2-one

Example 2.1 was repeated, using 72 mg of cuprous oxide (0.5 mmoles), 584mg of Chxn-Py-Al (2 mmoles), 951 mg of 2-hydroxypyridine (0 mmoles),6.52 g of caesium carbonate (20 mmoles), 3 g of ground and activated 3 Amolecular sieve, 1.68 ml of iodobenzene (15 mmoles) and 6 ml ofacetonitrile.

[0756] The degree of transformation of 1-phenyl-1H-pyridin-2-one was98%.

[0757] The residue obtained was purified by silica gel chromatography(eluent: hexane/dichloromethane/ethyl acetate, 100/0/0 to 0/100/0 then0/100/0 to 0/80/20).

[0758] 1.54 g of a yellow solid was obtained, corresponding to a yieldof 90%.

[0759] The compound obtained had the following formula:

[0760] The characteristics were as follows:

[0761] M.Pt: 127° C. (Lit: 129° C., diisopropyl ether, given by Ukita,T; Sugahara, M; Chem. Pharm. Bull. 1997, 45, 719-721);

[0762]¹H NMRIDMSO-d₆: δ 7.59-7.66 (m, 1H, HI,), 7.36-7.56 (m, 6H,H_(2-6,8)), 6.48 (m, 1H, H₉), 6.31 (m, 1H, H₇);

[0763]¹³C NMR/CDCl₃: δ 162.41 (C10), 140.97 (C1), 139.88 (C11), 138.01(C8), 129.34 (C4 and C5), 128.48 (C6), 126.54 (C2 and C3), 121.91 (C9),105.93 (C7);

[0764] GC/MS: Rt=18.11 min, M/Z=171, purity=99%;

[0765] Rf: 0.14 (eluent: dichloromethane/ethyl acetate, 90/10).

Example 2.4

[0766] Preparation of benzanilide (N-phenylbenzamide)

Example 2.1 was repeated, replacing the oxazolidin-2-one with 363 mg ofbenzamide (3 mmoles) and taking the reaction time to 48 h.

[0767] The degree of transformation of N-phenylbenzamide was 96% and theselectivity reached 100%.

[0768] The residue obtained was purified by silica gel chromatography(eluent: hexane/dichloromethane, 50/50 to 100/0).

[0769] 359 mg of a colourless solid was obtained, corresponding to ayield of 91%.

[0770] The compound obtained had the following formula:

[0771] The characteristics were as follows:

[0772] M.Pt: 164° C. (Lit: 163° C., EtOH, given by Goswami, B N;Borthakur, N, Ghosh, A C; J. Chem. Research (S), 1998, 268-269);

[0773]¹H NMR/CDCl₃: δ 7.88 (wide s, 1H, NH), 7.86 (m, 2H, H_(7,10)),7.64 (m, 2H, H_(6,9)), 7.32-7.58 (m, 5H, H_(1,2,5,11,12)) 7.15 (m, 1H,H₁₃). Purity =99%;

[0774]¹³C NMR/CDCl₃: δ 165.81 (C4), 137.96 (C3), 135.03 (C8), 131.83(C5), 129.09 (C11 and C12), 128.78 (C7 and C10), 127.04 (C6 and C9),124.58 (C13), 120.27 (C1 and C2);

[0775] GC/MS: Rt=20.76 min, M/Z=197;

[0776] Rf: 0.45 (eluent: dichloromethane).

Example 2.5

[0777] Preparation of 1-phenylpyrrolidin-2-one

Example 2.1 was repeated, replacing the oxazolidin-2-one with 152 μl ofpyrrolidin-2-one (2 mmoles) and operating with 336 μl of iodobenzene (3mmoles), the latter being added at the same time as thepyrrolidin-2-one.

[0778] The reaction time was taken to 40 h.

[0779] The degree of transformation and selectivity for1-phenylpyrrolidin-2-one were 100%.

[0780] The residue obtained was purified by silica gel chromatography(eluent: hexane/dichloromethane/ethyl acetate, 50/50/0 to 0/95/5).

[0781] 297 mg of a colourless solid was obtained, corresponding to ayield of 92%.

[0782] The compound could also be isolated by re-crystallising theresidue obtained from the solvent extraction steps from ethanol ratherthan using silica chromatography.

[0783] 265 mg of a beige solid was obtained, corresponding to a yield of82%.

[0784] The compound obtained had the following formula:

[0785] The characteristics were as follows:

[0786] M.Pt: 69-70° C. (Lit: 70° C., diisopropyl ether, given by Ukita,T; Sugahara, M; Chem. Pharm. Bull. 1997, 45, 719-721);

[0787]¹H NMR/CDCl₃: δ 7.58-7.63 (m, 2H, H_(2,6)), 7.32-7.40 (m, 2H,H_(3, 5)), 7.13-7.18 (m, 1H, H₄), 3.87 (m, 2H, H10) 2.61 (m, 2H, H₈),2.08-2.23 (m, 2H, H₉);

[0788]³C NMR/CDCl₃: a 174.20 (C7), 139.43 (C1), 128.81 (C2 and C6),124.48 (C4), 119.96 (C3 and C5), 48.78 (C10), 32.76 (C8), 18.03 (C9);

[0789] GC/MS: Rt=17.38 min, M/Z=161, Purity=99%;

[0790] Rf: 0.53 (eluent: dichloromethane/ethyl acetate, 80/20).

Example 2.6

[0791] Preparation of N-phenylbenzenesulphonamide

Example 2.1 was repeated, using 14.4 mg of cuprous oxide (0.1 mmoles),117 mg of Chxn-Py-Al (0.4 mmoles), 472 mg of benzenesulphonamide (3mmoles), 224 μl of iodobenzene (2 mmoles), 1.04 g of caesium carbonate(3.2 mmoles), 600 mg of ground and activated 3 Å molecular sieve and 1.6ml of DMF.

[0792] The reaction time was taken to 48 h.

[0793] The degree of transformation of N-phenylbenzenesulphonamide was95%.

[0794] After this reaction period, the reaction mixture was diluted with25 ml of dichloromethane/methanol and filtered through celite.

[0795] The residue obtained was purified by silica gel chromatography(eluent: hexane/dichloromethane, 90/10 to 5/95).

[0796] 411 mg of a colourless solid was obtained, corresponding to ayield of 88%.

[0797] The compound obtained had the following formula:

[0798] The characteristics were as follows:

[0799] M.Pt: 109-110° C. (Lit: 110° C., given by Hellwinkel, D; Supp, M;Chem. Ber. 1976, 109, 3749-3766);

[0800]¹H NMR/CDCl₆: δ 7.78-7.88 (m, 2H, H_(1,2)), 7.79 (broad s, 1H,NH), 7.35-7.50 (m, 3H, H_(3,5)), 7.07-7.25 (m, 5H, H₈₋₁₂);

[0801]¹³C NMR/CDCl₃: δ 138.89 (C6), 136.58 (C7), 133.10 (C5), 129.34 (C3and C4), 129.10 (C9 and C11), 127.29 (C1 and C2), 125.33 (C10), 121.55(C8 and C12);

[0802] GC/MS: Rt=21.54 min, M/Z=233, purity=99%;

[0803] Rf: 0.36 (eluent: dichloromethane).

Example 3 Arylation of Ethers General Operating Protocol

[0804] The following are successively introduced into a 35 ml Schlenktube placed in a nitrogen atmosphere:

[0805] Cuprous oxide (0.1 mmoles);

[0806] ligand (0.4 mmoles);

[0807] nucleophilic compound (2 mmoles);

[0808] a base (4 mmoles);

[0809] 3 mmoles of arylation agent;

[0810] and 1.2 ml of acetonitrile.

[0811] The mixture is placed in an oil bath at a temperature of 82° C.and stirred for 24 hours.

[0812] Determination of Isolated Yield:

[0813] After the period, the reaction mixture is diluted with 25 ml ofdichloromethane, filtered through celite, concentrated completely underreduced pressure then taken up in 50 ml of dichloromethane.

[0814] This organic phase is extracted with distilled water (2×20 ml).

[0815] The aqueous phase is extracted again with 20 ml ofdichloromethane.

[0816] The total organic phase is washed with a saturated aqueous sodiumchloride solution (2×20 ml), dried over MgSO₄, filtered and concentratedunder reduced pressure.

[0817] The residue obtained is purified by silica gel chromatography(35-70 μm).

[0818] Determination of Degree of Transformation:

[0819] After the period, 65 μl of 1,3-dimethoxybenzene (internalreference) is introduced into the cooled reaction medium, which is thendiluted with 5 ml of diethyl ether or dichloromethane, depending on thesolubility of the products to be analysed.

[0820] An aliquot is then removed, filtered through celite, eluting withdiethyl ether or dichloromethane, extracted three times with distilledwater then analysed by gas chromatography.

Example 3.1 Preparation of Diphenyl Ether

[0821] 14.4 mg of cuprous oxide (0.1 mmoles), 117 mg of Chxn-Py-Al (0.4mmoles), 188 mg of phenol (2 mmoles), 1.303 g of caesium carbonate (4mmoles) and 600 mg of ground and activated 3 A molecular sieve(K_(n)Na_(12-n)[(AlO₂)₁₂(SiO₂)12]) were successively introduced into a35 ml Schlenk tube that had been oven dried at 100° C. and provided witha magnetic stirrer (12×4.5 mm) and under a nitrogen atmosphere.

[0822] The Schlenk tube was purged under vacuum then refilled withnitrogen.

[0823] 336 μl of iodobenzene (3 mmoles) then 1.2 ml of acetonitrile wereadded using syringes.

[0824] The reactor was placed in an oil bath at a temperature of 82° C.and stirred for a period of 24 hours.

[0825] The degree of transformation and the selectivity for diphenylether were 100%.

[0826] After this period, the reaction mixture was diluted with 25 ml ofdichloromethane, filtered through celite, concentrated completely underreduced pressure then taken up in 50 ml of dichloromethane.

[0827] This organic phase was extracted with distilled water (2×20 ml).

[0828] The aqueous phase was extracted again with 20 ml ofdichloromethane.

[0829] The total organic phase was washed with a saturated aqueoussodium chloride solution (2×20 ml), dried over MgSO₄, filtered andconcentrated under reduced pressure.

[0830] The oily residue obtained after treatment was complete waspurified by silica gel chromatography (eluent: hexane).

[0831] 344 mg of a colourless oil was obtained (corresponding to a yieldof 100%), which crystallised out after a few hours in the refrigerator(colourless crystals).

[0832] The compound obtained had the following formula:

[0833] The characteristics were as follows:

[0834] M.Pt: 26° C. (Lit: 85° C., given by Byers, C H; Williams, D F; J.Chem. Eng. Data 1987, 32, 344-348);

[0835]¹H NMR/CDCl₃: δ 7.37-7.47 (m, 4H, H_(2,4,9,11)), 7.10-7.23 (m, 6H,H_(1,3,5,10,12));

[0836]¹³C NMR/CDCl₃: δ 157.38 (C6 and C7), 129.88 (C2, C4, C9 and C11),123.35 (C3 and C10), 119.02 (C1, C5, C8 and C12);

[0837] GC/MS: Rt=14.43 min, M/Z=170, purity=99%;

[0838] Rf: 0.33 (eluent: hexane).

Example 3.2

[0839] Preparation of 4-methoxyphenyl Phenyl Ether

[0840] Example 3.1 was repeated, replacing the phenol with 248 mg of4-methoxyphenol (2 mmoles) and heating for 28 h at 82° C.

[0841] The degree of transformation and the selectivity for4-methoxyphenyl phenyl ether were 100%.

[0842] The orange oil obtained after treatment was complete was purifiedby silica gel chromatography (eluent: hexane/dichloromethane, 100/0 to95/5).

[0843] 380 mg of a colourless oil was obtained, which corresponded to ayield of 95%.

[0844] The compound obtained had the following formula:

[0845] The characteristics were as follows:

[0846]¹H NMR/CDCl₃: δ 7.30-7.39 (m, 2H, H_(2,4)), 6.89-7.09 (m, 7H,H_(1,3,5,8,9,11,12)), 3.84 (s, 3H, H₁₃);

[0847]¹³C NMR/CDCl₃: δ 158.60 (C6), 155.97 (C10), 150.18 (C7), 129.69(C2 and C4), 122.49 (C3), 120.91 (C8 and C12), 117.64 (C1 and C5),114.92 (C9 and C11), 55.67 (C13);

[0848] GC/MS: Rt=17.67 min, M/Z=200, purity=95.5%;

[0849] Rf: 0.25 (eluent: hexane/dichloromethane, 80/20).

Example 3.3

[0850] Preparation of 4-t-butylphenyl Phenyl Ether

[0851] Example 3.1 was repeated, replacing the phenol with 300 mg of4-t-butylphenol (2 mmoles).

[0852] The degree of transformation and the selectivity for4-t-butylphenyl phenyl ether were 100%.

[0853] The oily residue obtained after treatment was complete waspurified by silica gel chromatography (eluent: hexane).

[0854] 430 mg of a colourless oil was obtained (which corresponded to ayield of 95%), which crystallised after a few hours in the refrigerator(colourless crystals).

[0855] The compound obtained had the following formula:

[0856] The characteristics were as follows:

[0857] M.Pt: 52° C. (Lit: 53-54° C., given Harvey, L; Gleicher, G J;Totherow, W D; Tetrahedron 1969, 25, 5019-5026);

[0858]¹H NMR/DMSO-d₆: δ 7.33-7.41 (m, 4H, H_(2,4,8,12)), 7.06-7.14 (m,1H, H₃), 6.91-6.99 (m, 4H, H_(1,5,9,11)), 1.27 (s, 9H, H_(14,15,16));

[0859]¹³C NMR/DMSO-d₆: δ 156.94 (C6), 154.09 (C7), 145.73 (C10), 129.88(C2 and C4), 126.61 (C9 and C11), 123.05 (C3), 118.21 (C1, C5, C8 andC12), 33.96 (C13), 31.18 (C14, C15 and C16).

[0860] GC/MS: Rt=18.50 min, M/Z=226, purity=98.5%;

[0861] Rf: 0.36 (eluent: hexane).

Example 3.4

[0862] Preparation of 3,5-dimethylphenyl Phenyl Ether

[0863] Example 3.1 was repeated, replacing the phenol with 244 mg of3,5-dimethylphenol (2 mmoles).

[0864] The degree of transformation and the selectivity for3,5-dimethylphenyl phenyl ether were 100%.

[0865] The brown oil obtained after treatment was complete was purifiedby silica gel chromatography (eluent: hexane).

[0866] 381 mg of a colourless oil was obtained, which corresponded to ayield of 97%.

[0867] The compound obtained had the following formula:

[0868] The characteristics were as follows:

[0869]¹H NMR/CDCl₃: δ 7.28-7.42 (m, 2H, H_(2,4)), 7.12-7.17 (m, 1H, H₃),7.03-7.14 (m, 2H, H_(1,5)), 6.79 (m, 1H, H₁₀), 6.69 (m, 2H, H_(8,12)),2.33 (s, 6H, H_(13,14));

[0870]¹³C NMR/CDCl₃: δ 157.50 (C6), 157.22 (C7), 139.61 (C9 and C11),129.70 (C2 and C4), 125.04 (C10), 123.02 (C3), 118.89 (C1 and C5),116.67 (C8 and C12), 21.35 (C13);

[0871] GC/MS: Rt=16.87 min, M/Z=198, purity=98%;

[0872] Rf: 0.19 (eluent: hexane).

Example 3.5 Preparation of 3,5-dimethylphenyl Phenyl Ether fromBromobenzene

[0873] Example 3.3 was repeated, replacing the iodobenzene withbromobenzene (316 μl, 3 mmoles), the acetonitrile with DMF, and heatingfor 24 h at 110° C.

[0874] The degree of transformation of 3,5-dimethylphenyl ether was 70%.

[0875] The degree of transformation of 3,5-dimethylphenyl ether was 100%after heating for 72 h under these conditions.

Example 3.6

[0876] Preparation of 3,5-dimethylphenyl 4-trifluoromethylphenyl Ether

[0877] Example 3.1-was repeated, replacing the phenol with 244 mg of3,5-dimethylphenol (2 mmoles) and the iodobenzene with 294 μl of4-iodotrifluoromethylbenzene (2.6 mmoles).

[0878] The degree of transformation and the selectivity for3,5-dimethylphenyl 4-trifluoromethylphenyl ether were 100%.

[0879] The residue obtained after treatment was complete was purified bysilica gel chromatography (eluent: hexane).

[0880] 506 mg of an orange oil was obtained, which corresponded to ayield of 95%.

[0881] The compound obtained had the following formula:

[0882] The characteristics were as follows:

[0883]¹H NMR/CDCl₃: δ 7.59 (m, 2H, H_(2,4)), 7.06 (m, 2H, H_(1,5)), 6.87(m, 1H, H₁₀), 6.71 (m, 2H, H_(8,12)), 2.35 (s, 6H, H_(13,14));

[0884]¹³C NMR/CDCl₃: δ 160.78 (C6), 155.65 (C7), 140.01 (C9 and C11),127.04 (q, ³J_(CF)=3.8 Hz, C2 and C4), 126.25 (C10), 124.59 (q,²J_(CF)=32.7 Hz, C3), 118.92 (q, ¹J_(CF)=271.1 Hz, C15), 117.78 (C8 andC12), 117.63 (C1 and C5), 21.26 (C13 and C14);

[0885]¹⁹F NMR/CDCl₃: δ−62.11 (CF₃);

[0886] Elemental analysis: Calculated: C: 67.66%; H: 4.92%; F: 21.41%.Found: C: 67.37%; H: 5.03%; F: 21.80%;

[0887] GC/MS: Rt=16.71 min, M/Z=266, purity=99%;

[0888] IR (CH₂Cl₂): 3053 (VW, aromatic), 2985 (VW), 1615, 1591 and 1513(W, aromatic C═C), 1326 (VS, CF₃), 1237 (S, C—O), 1169 (S, CF₃), 1123(S), 1066 (S), 840 (W), 748 (VS), 730 (S).

[0889] Rf: 0.68 (eluent: hexane).

Example 3.7

[0890] Preparation of 3.5-dimethylphenyl 2-methylphenyl Ether

[0891] Example 3.1 was repeated, replacing the phenol with 244 mg of3,5-dimethylphenol (2 mmoles) and the iodobenzene with 383 μl of2-iodotoluene (3 mmoles), and taking the reaction time to 118 hours.

[0892] The degree of transformation and the selectivity for3,5-dimethylphenyl 2-methylphenyl ether were 100%.

[0893] The oily residue obtained after treatment was complete waspurified by silica gel chromatography (eluent: hexane).

[0894] 399 mg of a colurless oil was obtained, which corresponded to ayield of 94%.

[0895] The compound obtained had the following formula:

[0896] The characteristics were as follows:

[0897]¹H NMR/CDCl₃: δ 7.08-7.33 (m, 3H, H_(2,3,4)), 6.95-6.99 (m, 1H,H₁), 6.76 (m, 1H, H₁₀), 6.61 (m, 2H, H_(8,12)), 2.33 (s, 6H, H_(13,14)),2.32 (s, 3H, H₁₅) [Buchwald, S L; Marcoux, J-F; Doye, S; J. Am. Chem.Soc. 1997, 119, 10539-10540, Supporting Information);

[0898]¹³C NMR/CDCl₃: δ 157.94 (C6), 154.69 (C7), 139.55 (C9 and C11),131.41 (C2), 130.02 (C5), 127.14 (C4), 124.22 (C10), 123.83 (C3), 119.81(C1), 115.11 (C8 and C12), 21.42 (C13 and C14), 16.30 (C15);

[0899] GC/MS: Rt=17.46 min, M/Z=212, purity=99.7%;

[0900] Rf: 0.26 (eluent: hexane).

Example 3.8

[0901] Preparation of 3.5-dimethylphenyl 4-methoxyphenyl Ether

[0902] Example 3.1 was repeated, replacing the phenol with 244 mg of3,5-dimethylphenol (2 mmoles) and the iodobenzene with 655 mg of4-iodoanisole (2.8 mmoles), the latter being added at the same time asthe 3,5-dimethylphenol, and taking the reaction time to 48 hours.

[0903] The degree of transformation and the selectivity for3,5-dimethylphenyl 4-methoxyphenyl ether were 100%.

[0904] The residue obtained after treatment was placed in an oven at100° C. to evaporate off the anisole, then it was purified by silica gelchromatography (eluent: hexane).

[0905] 420 mg of a colourless oil was obtained, which corresponded to ayield of 92%.

[0906] Crystals could be obtained after re-crystallisation frompetroleum ether.

[0907] The compound obtained had the following formula:

[0908] The characteristics were as follows:

[0909] M.Pt: 67° C. (Lit: 67° C., given by Walter; Barell-Festschr.,Basel 1936, 266-273);

[0910]¹H NMR/CDCl₃: δ 6.99-7.06 (m, 2H, H_(2,4)), 6.88-6.99 (m, 2H,H_(1,5)), 6.74 (m, 1H, H10), 6.64 (m, 2H, H_(8,12)), 3.85 (s, 3H, H₁₅),2.32 (s, 6H, H_(13,14));

[0911]³C NMR/CDCl₃: δ 158.52 (C3), 155.76 (C7), 150.26 (C6), 139.45 (C9and C11), 124.22 (C10), 120.84 (C1 and C5), 115.31 (C2 and C4), 114.77(C8 and C12), 55.59 (C15), 21.35 (C13 and C14);

[0912] GC/MS: Rt=19.77 min, M/Z=228, purity=99%;

[0913] Rf: 0.61 (eluent: hexane).

Example 3.9

[0914] Preparation of 3,5-dimethylphenyl 4-cyanophenyl Ether

[0915] Example 3.1 was repeated, replacing the phenol with 244 mg of3,5-dimethylphenol (2 mmoles) and the iodobenzene with 595 mg of4-iodobenzonitrile (2.6 mmoles), the latter being added at the same timeas the 3,5-dimethylphenol.

[0916] The degree of transformation and the selectivity for3,5-dimethylphenyl 4-cyanophenyl ether were 100%.

[0917] The residue obtained after treatment was placed in an oven at100° C. to evaporate off the benzonitrile then it was purified by silicagel chromatography (eluent: hexane/dichloromethane, 100/0 to 50/50).

[0918] 415 mg of an orange solid was obtained, which corresponded to ayield of 93%.

[0919] The compound obtained had the following formula:

[0920] The characteristics were as follows:

[0921] M.Pt: 58° C.;

[0922]¹H NMR/CDCl₃: δ 7.53-7.60 (m, 2H, H_(2,4)), 6.95-7.00 (m, 2H,H_(1,5)), 6.86 (m, 1H, H₁₀), 6.68 (m, 2H, H_(8,12)), 2.32 (s, 6H,H_(13,14));

[0923]¹³C NMR/CDCl₃: δ 161.90 (C6), 154.76 (C7), 140.17 (C9 and Cl1),134.07 (C2 and C4), 126.86 (C10), 118.92 (C15), 118.03 (C1 and C5),117.88 (C8 and C12), 105.55 (C3), 21.28 (C13 and C14);

[0924] GC/MS: Rt=20.54 min, M/Z=223, purity=100%;

[0925] Rf: 0.32 (eluent: hexane/dichloromethane, 50/50).

Example 3.10

[0926] Preparation of bis(o-tolyl) Ether

[0927] Example 3.1 was repeated, replacing the phenol with 206 μl ofo-cresol (2 mmoles) and the iodobenzene with 383 μl of 2-iodotoluene (3mmoles), the acetonitrile with DMF, and with the nucleophile and thearylation agent being added at the same time as the solvent.

[0928] The reaction time was taken to 35 h and the temperature was 110°C.

[0929] The degree of transformation and the selectivity for bis(o-tolyl)ether were 100%.

[0930] The oily residue obtained after treatment purified by silica gelchromatography (eluent: hexane).

[0931] 389 mg of a colourless oil was obtained, which corresponded to ayield of 98%.

[0932] The compound obtained had the following formula:

[0933] The characteristics were as follows:

[0934]¹H NMR/CDCl₃: δ 7.32 (m, 2H, H_(2,11)), 7.04-7.25 (m, 4H,H_(3,4,9,10)), 6.81 (m, 2H, H_(5,8)), 2.38 (s, 6H, H_(13,14));

[0935]¹³C NMR/CDCl₃: δ 155.35 (C6 and C7), 131.39 (C4 and C9), 128.90(C1 and C12), 127.09 (C2 and C11), 123.11 (C3 and C10), 117.74 (C5 andC8), 16.25 (C13 and C14);

[0936] GC/MS:Rt=16.10 min, M/Z=198, purity=100%;

[0937] Rf: 0.40 (eluent: hexane).

Example 3.11

[0938] Preparation of phenyl 2-methylphenyl Ether

[0939] Example 3.1 was repeated, replacing the phenol with 206 μl ofo-cresol (2 mmoles), and with the nucleophile and the arylation agentbeing added at the same time as the solvent.

[0940] The reaction time was taken to 40 h.

[0941] The degree of transformation and the selectivity for phenyl2-methylphenyl ether were 100%.

[0942] The oily residue obtained after treatment was purified by silicagel chromatography (eluent: hexane).

[0943] 343 mg of a colourless oil was obtained, which corresponded to ayield of 93%.

[0944] The compound obtained had the following formula:

[0945] The characteristics were as follows:

[0946]¹H NMR/CDCl₃: δ 7.19-7.35 (m, 3H, H_(4,9,11)), 7.00-7.18 (m, 3H,H_(2,3,10)), 6.87-6.94 (m, 3H, H_(1,8,12)), 2.25 (s, 3H, H₁₃);

[0947]¹³C NMR/CDCl₃: δ 158.08 (C7), 54.60 (C6), 131.60 (C2), 130.14(C5), 129.81 (C9 and C11), 127.30 (C4), 124.15 (C10), 122.48 (C3),119.94 (C1), 141 17.44 (C8 and C12), 16.35 (C13);

[0948] GC/MS: Rt=15.25 min, M/Z=184, purity=98%;

[0949] Rf: 0.36 (eluent: hexane).

Example 3.12

[0950] Preparation of 3,5-dimethylphenyl 2-pyridyl Ether

[0951] General procedure A (110° C., 24 hours) was followed using 117 mgof Chxn-Py-Al (0.4 mmoles), 292 μl of 2-bromopyridine (3 mmoles), 244 mgof 3,5-dimethylphenol (2 mmoles), 600 mg of ground and activated 3 Åmolecular sieve and 1.2 ml of DMF.

[0952] The oil obtained after the filtering step was oven dried for twohours at 100° C. to evaporate off the 2-pyridylaldehyde then purified bysilica gel chromatography (eluent: hexane/dichloromethane, 100/0 to85/15).

[0953] 371 mg of a yellow oil was obtained, which corresponded to ayield of 93%.

[0954] The compound obtained had the following formula:

[0955] The characteristics were as follows:

[0956]¹H NMR/CDCl₃: δ 8.21 (ddd, 1H, ³J_(HH)=5.0 HZ, ⁴J_(HH)=2.0 Hz,⁵J_(HH)=0.7 Hz, H₂), 7.66 (ddd, 1H, ³J_(HH)=8.2 Hz, ³J_(HH)=7.2 Hz,⁴J_(HH)=2.0 HZ, H₄),6.97 (ddd, 1H¹³J_(HH)=7.2 HZ, ³J_(HH)=5.0 Hz,⁴J_(HH)=0.9 Hz, H₃), 6.88 (ddd, 1H, ³J_(HH)=8.2 Hz, ⁴J_(HH)=0.9 Hz,⁵J_(HH)=0.7 Hz, H₅), 6.84 (m, 1H, H10), 6.76 (m, 2H, H_(6,8)), 2.32 (s,6H, H_(12,13));

[0957]¹³C NMR/CDCl₃: δ 164.02 (C1), 154.15 (C7), 147.87 (C2), 139.47 (C9and Cl 1), 139.27 (C4), 126.53 (C10), 118.80 (C6 and C8), 118.22 (C5),111.47 (C3), 21.34 (C12 and C13);

[0958] Elemental analysis: Calculated: C: 78.21%; H: 6.69%; N: 7.04%.Found C: 78.36%; H: 6.58%; N: 7.03%;

[0959] GC/MS: Rt=17.65 min, M/Z=199, purity=99%;

[0960] IR (CH₂Cl₂): 3027 (VW, aromatic), 1468 and 1430 (VW, aromaticC═C), 1220 (S, C—O), 781 (S), 759 (VS), 751 (S);

[0961] Rf: 0.22 (eluent: hexane/dichloromethane, 75/25).

Example 4

[0962] Arylation of Carbon-Containing Nucleophiles

Example 4.1 Synthesis of Diethyl 2-phenylmalonate

[0963] 38 mg of cuprous iodide (0.2 mmoles), 117 mg of Chxn-Py-Al (0.4mmoles) and 977 mg of caesium carbonate (3 mmoles) were successivelyintroduced into a 35 ml Schlenk tube that had been oven dried at 100° C.and provided with a magnetic stirrer (12×4.5 mm) and under a nitrogenatmosphere.

[0964] The Schlenk tube was purged under vacuum then refilled withnitrogen.

[0965] 607 μl of diethyl malonate (3 mmoles), 224 μl of iodobenzene (2mmoles), 1.2 ml of acetonitrile and 600 mg of ground and activated 3 Amolecular sieve were then added.

[0966] The reactor was placed in an oil bath at a temperature of 70° C.and stirred for a period of 30 hours.

[0967] A compound with the following formula was obtained:

[0968] The characteristics were as follows:

[0969]¹H NMR/CDCl₃: δ 7.32-7.42 (m, 5H, H₁₅), 4.62 (s, 1H, H₇), 4.22 (m,4H, H_(10,11)), 1.26 (t, ³J_(HH)=7.1 Hz, 6H, H_(12,13));

[0970]¹³C NMR/CDCl₃: δ 168.15 (C8 and C9), 132.86 (C6), 129.27 (C2 andC3), 128.58 (C4 and C5), 128.18 (C1), 61.77 (C1I and C12), 58.00 (C7),14.00 (C12 and C13);

[0971] GC/MS: Rt=16.77 min, M/Z=236, purity=99%;

[0972] Rf: 0.27 (eluent: hexane/dichloromethane, 70/30).

1. A process for arylating or vinylating or alkynating a nucleophiliccompound, consisting of reacting said compound with a compound carryinga leaving group, characterized in that the reaction is carried out inthe presence of an effective quantity of a catalyst based on a metallicelement M selected from groups (VIII), (Ib) and (IIb) of the periodictable and at least one ligand comprising at least one imine function andat least one supplemental nitrogen atom as chelating atoms.
 2. A processaccording to claim 1, characterized in that the ligand is bidentate,tridentate or tetradentate in type.
 3. A process according to claim 2,characterized in that the ligand employed has the following formulae:

in which formulae: one of groups R_(a) and R_(b) can comprise at leastone nitrogen atom or a group comprising a nitrogen atom; R_(a) and R_(b)independently represent a hydrocarbon group containing 1 to 20 carbonatoms, which may be a linear or branched, saturated or unsaturated,acyclic aliphatic group; a monocyclic or polycyclic, saturated,unsaturated or aromatic carbocyclic or heterocyclic group; or aconcatenation of said groups; or R_(a) and R_(b) can be bonded toconstitute, with the carbon atoms carrying them, a monocyclic orpolycyclic, saturated or unsaturated, carbocyclic or heterocyclic groupcontaining 3 to 20 atoms; R_(c) represents an alkyl group, preferably C₁to C₁₂; an alkenyl or alkynyl group, preferably C₂ to C₁₂; a cycloalkylgroup, preferably C₃ to C₁₂; an aryl or arylalkyl group, preferably C₆to C₁₂, an amido group —CO—NH₂; an amido group substituted with one ortwo alkyl groups, preferably C₁ to C₁₂; and/or an alkenyl or alkynylgroup, preferably C₂ to C₁₂; and/or a cycloalkyl group, preferably C₃ toC₁₂; and/or an aryl or arylalkyl group, preferably C₆ to C₁₂.
 4. Aprocess according to claim 3, characterized in that the ligand hasformula (Ia₁) or (Ia₂) in which R_(c), which may be identical ordifferent, represent a hydrogen atom or a methyl group and R_(a)represents one of the following groups:

in which R_(s) represents an alkyl or alkoxy group, preferably C₁ to C₄,or an amino group which may or may not be substituted with an alkylgroup, preferably C₁ to C₄.
 5. A process according to claim 2,characterized in that the ligand employed has the following formulae:

in which formulae: R_(a), which may be identical or different, have themeanings given in formulae (Ia₁) and (Ia₂); R_(b), which may beidentical or different, have the meanings given in formulae (Ia₁) and(Ia₂); ψ represents a —HN—CO—NH— group or a skeleton with generalformula (F2) or (F₃):

in which formulae (F₂) and (F₃): R_(f) and R_(g) independently representa hydrocarbon group containing 1 to 20 carbon atoms, which may be alinear or branched, saturated or unsaturated acyclic aliphatic group; amonocyclic or polycyclic, saturated, unsaturated or aromatic carbocyclicor heterocyclic group; or a concatenation of said groups; or R_(f) andR_(g) can be bonded together to constitute, with the carbon atomscarrying them, a carbocyclic or heterocyclic group containing 3 to 20atoms, which may be saturated, unsaturated, monocyclic or polycyclic;Ar₁ and AR₂ independently represent two substituted or non substitutedaromatic, carbocyclic or heterocyclic cycles which may or may not becondensed, which may carry one or more heteroatoms; x and y respectivelyrepresent the two bonds between the skeleton shown as 4 and the iminegroups.
 6. A process according to claim 5, characterized in that theligand has formulae (Ib₁) or (Ib₂) in which R_(b) represents a hydrogenatom and R_(a) represents one of the following groups:

in which R_(s) represents an alkyl or alkoxy group, preferably C₁ to C₄,or an amino group which may or may not be substituted with alkyl groups,preferably C₁ to C₄.
 7. A process according to claim 5 or claim 6,characterized in that the ligand has formula (Ib₁) or (Ib₂), in which ψrepresents the following cyclic groups:


8. A process according to claim 2, characterized in that the ligand hasthe following formula:

in which formula: R_(a), which may be identical or different, have themeanings given in formulae (Ian) and (Ia₂); Φ represents: a covalentbond; an alkylene group with formula:

in which R_(c), R_(d), which may be identical or different, represent: ahydrogen atom; a linear or branched alkyl group containing 1 to 12carbon atoms, optionally carrying a halogen atom, preferably 1 to 4carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl or tert-butyl; a halogen atom; and m equals 0, 1 or 2,preferably 0 or 1; or the residue of a monocyclic or polycyclichydrocarbon cycle containing 5 to 12 carbon atoms carrying the two iminefunctions in the ortho or meta position.
 9. A process according to claim8, characterized in that the ligand has formula (Ic₁) in which groupsR_(a) are identical and represent one of the following groups:

in which R_(s) represents an alkyl group, preferably C₁ to C₄.
 10. Aprocess according to claim 8, characterized in that the ligand formula(Ic₁) in which Φ represents a covalent bond, a methylene or ethylenegroup, or a divalent cyclic group such as:


11. 12. A process according to claim 1, characterized in that the ligandis selected from :Ph-Alzone, Py-Alzone, N-Methyl-Py-Alzone,N-Dimethyl-Py-Alzone, N-Amido-Py-Alone, Chxn-Phenyl-Al, Chxn-Py-AlmCarbo-Py-Al, Chxn-Thio-Al, DAB-Cy.
 13. A process according to one claims11 to 11, characterized in that the quantity of ligand employed is suchthat the ratio between the number of moles of ligand and the number ofmoles of metal is in the range 2 to
 1. 14. A process according to one ofclaims 1 to 13, characterized in that the nucleophilic substrate is anorganic hydrocarbon compound that may be acyclic or cyclic thecharacteristic of which is that it comprises at least one atom carryinga free electron pair which may or may not carry a charge, preferably anitrogen, oxygen, sulphur, phosphorus or carbon atom.
 15. A processaccording to one of claims 1 to 14, characterized in that thenucleophilic substrate comprises at least one of the following atoms orgroups:


16. A process according to one of claims 1 to 14, characterized in thatthe nucleophilic substrate comprises at least one nitrogen atom carryinga free electron pair included in a saturated, unsaturated or aromaticcycle: the cycle generally comprising 3 to 8 atoms.
 17. A processaccording to claim 14, characterized in that the nucleophilic substrateis a primary or secondary amine; a hydrazine or hydrazone derivative; anamide; a sulphoamide; a urea derivative; or a heterocyclic derivative,preferably nitrogen- and/or sulphur-containing.
 18. A process accordingto claim 14, characterized in that the nucleophilic substrate has thefollowing formula:

in which formula (IIIh): A represents the residue of a cycle forming allor a portion of a monocyclic or polycyclic, aromatic or non aromaticheterocyclic system wherein one of the carbon atoms is replaced by atleast one nucleophilic atom such as a nitrogen, sulphur or phosphorusatom; R₁₂, which may be identical or different, represent substituentson the cycle; n represents the number of substituents on the cycle. 19.A process according to claim 18, characterized in that the nucleophilicsubstrate has formula (IIIh) in which A represents a cycle such as:imidazole, pyrazole, triazole, pyrazine, oxadiazole, oxazole, tetrazole,indole, pyrole, phthalazine, pyridazine or oxazolidine.
 20. A processaccording to claim 14, characterized in that the nucleophilic substrateis an alcohol or thiol type compound, preferably a hydroxy- orthioaromatic type compound.
 21. A process according to claim 20,characterized in that the nucleophilic substrate has the followingformula:

in which: B represents the residue of a monocyclic or polycyclic,aromatic carbocyclic group or a divalent group constituted by aconcatenation of two or more monocyclic aromatic carbocyclic groups; R₁₄represents one or more substituents, which may be identical ordifferent; Z represents a hydroxyl or thiol group; n′ is 5 or less. 22.A process according to claim 14, characterized in that the nucleophilicsubstrate is a hydrocarbon compound containing a nucleophilic carbon,preferably a malonate, malodintrile, nitrile, acetylenide, profene typecompound or amino acid.
 23. A process according to claim 14,characterized in that the nucleophilic substrate is a phosphide,phosphine, phosphonium diazaylide, phosphonium azaylide, boronic acid orderivative thereof.
 24. A process according to claim 23, characterizedin that the nucleophilic substrate is a boronic acid or a derivativewith the following formula:

in which: R₂₄ represents a monocyclic or polycyclic, aromatic,carbocyclic or heterocyclic group; Q₁, Q₂, which may be identical ordifferent, represent a hydrogen atom, a linear or branched, saturated orunsaturated aliphatic group containing 1 to 20 carbon atoms, or a R₂₄group.
 25. A process according to claim 24, characterized in that thearylboronic acid R₂₄ has formula (IIIt) in which R₂₄ represents anaromatic carbocyclic or heterocyclic group, preferably a phenyl ornaphthyl group, or a pyrrolyl, pyridyl, pyrimidyl, pyridazinyl,pyrazinyl, 1,3-thiazolyl, 1,3,4-thiadiazolyl or thienyl group.
 26. Aprocess according to claim 24 or claim 25, characterized in that thearylboronic acid has formula (IIIt) in which Q₁, Q₂, which may beidentical or different, represent a hydrogen atom or a linear orbranched acyclic aliphatic group containing 1 to 20 carbon atoms whichmay be saturated or contain one or more unsaturated bonds in the chain,preferably 1 to 3 unsaturated bonds, preferably simple or conjugateddouble bonds; or a group R₂₄, preferably a phenyl group.
 27. A processaccording to one of claims 1 to 26, characterized in that the compoundcarrying a leaving group Y is represented by formula (IV): R₀—Y  (IV) inwhich formula R₀ represents a hydrocarbon group containing 2 to 20carbon atoms and has a double bond or a triple bond located in theposition α to the leaving group Y, or a monocyclic or polycyclic,aromatic, carbocyclic and/or heterocyclic group.
 28. A process accordingto claim 27, characterized in that the compound carrying a leaving grouphas formula (IV) in which: R₀ represents an aliphatic hydrocarbon groupcontaining a double bond or a triple bond in the position α to theleaving group or a cyclic hydrocarbon group containing an unsaturatedbond carrying a leaving group; R₀ represents a monocyclic or polycyclic,aromatic, carbocyclic and/or heterocyclic group; Y represents a leavinggroup, preferably a halogen atom or a sulphonic ester group with formula—OSO₂—R_(e), in which R_(e) is a hydrocarbon group.
 29. A processaccording to claim 27 or claim 28, characterized in that the compoundcarrying a leaving group has formula (IV) in which Y represents abromine or chlorine atom or a sulphonic ester with formula —OSO₂—R_(e),in which R_(e) is a linear or branched alkyl group containing 1 to 4carbon atoms, preferably a methyl or ethyl group, a phenyl or tolylgroup or a trifluoromethyl group.
 30. A process according to one ofclaims 27 to 29, characterized in that the compound carrying a leavinggroup has formula (IV) and is selected from the following compounds: (1)aliphatic type compounds, carrying a double bond and which can berepresented by formula (IVa):

in which formula (IVa): R₂₅, R₂₆ and R₂₇, which may be identical ordifferent, represent a hydrogen atom or a hydrocarbon group containing 1to 20 carbon atoms, which can be a linear or branched, saturated orunsaturated aliphatic group; a monocyclic or polycyclic, saturated,unsaturated or aromatic carbocyclic or heterocyclic group; or aconcatenation of aliphatic and/or carbocyclic and/or heterocyclic groupsas defined above; Y represents the leaving group, as defined above; (2)aliphatic type compounds carrying a triple bond, represented by formula(IVb): R₂₅—C═C—Y  (IVb) in which formula (IVb): R₂₅ has the meaninggiven in formula (IVa); Y represents a leaving group as defined above;(3) aromatic type compounds which can be represented by formula (IVc):

in which: D represents the residue of a cycle forming all or a portionof a monocyclic or polycyclic, aromatic, carbocyclic and/or heterocyclicsystem; R₂₈, which may be identical or different, represent substituentson the cycle; Y represents a leaving group as defined above; n″represents the number of substituents on the cycle.
 31. A processaccording to one of claims 27 to 30, characterized in that the compoundcarrying a leaving group with formula (IV) is selected from: vinylchloride, vinyl bromide, bromoalkyne, iodoalkyne, β-bromostyrene,β-chlorostyrene, p-chlorotoluene, p-bromoanisole andp-bromotrifluorobenzene.
 32. A process according to one of claims 1 to31, characterized in that the catalyst comprises at least one of thefollowing metallic elements M: copper, silver, palladium, cobalt,nickel, iron and/or zinc.
 33. A process according to claim 32,characterized in that the catalyst is a copper catalyst, preferably acopper halide.
 34. A process according to one of claims 1 to 33,characterized in that the reaction is carried out in the presence of abase.
 35. A process according to claim 34, characterized in that thebase is selected from: alkali metal carbonates, bicarbonates orhydroxides, preferably sodium, potassium or caesium, and alkaline-earthmetal carbonates, bicarbonates or hydroxides, preferably calcium, bariumor magnesium; alkali metal hydrides, preferably sodium hydride; alkalimetal alcoholates, preferably sodium or potassium, more preferablysodium methylate, ethylate or tertiobutylate; and tertiary amines.
 36. Aprocess according to one of claims 1 to 35, characterized in that thereaction is carried out in the presence of an organic solvent.
 37. Aprocess according to claim 36, characterized in that the organic solventis selected from: linear or cyclic carboxamides; dimethylsulphoxide(DMSO); hexamethylphosphotriamide (HMPT); tetramethylurea; nitrocompounds; aliphatic or aromatic nitriles, preferably acetonitrile;tetramethylene sulphone; organic carbonates; alkyl esters; halogenatedaromatic hydrocarbons, preferably chlorobenzene or toluene; andnitrogen-containing heterocycles, preferably pyridine, picoline orquinolines.
 38. A process according to one of claims 1 to 37,characterized in that the temperature of the arylation or vinylation oralkynation reaction is in the range 0° C. to 120° C., preferably in therange 20° C. to 100° C., more preferably in the range 25° C. to 85° C.39. Novel compounds with formulae: